TWI236477B - beta-carboline compounds which bind to somatostatin receptors and block sodium channels - Google Patents

beta-carboline compounds which bind to somatostatin receptors and block sodium channels Download PDF

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TWI236477B
TWI236477B TW088109827A TW88109827A TWI236477B TW I236477 B TWI236477 B TW I236477B TW 088109827 A TW088109827 A TW 088109827A TW 88109827 A TW88109827 A TW 88109827A TW I236477 B TWI236477 B TW I236477B
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phenyl
alkyl
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hydrogen
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Christophe Alain Thurieau
Lydie Francine Poitout
Marie Odile Galcera
Thomas D Gordon
Barry A Morgan
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Sod Conseils Rech Applic
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Abstract

The present invention is directed to compounds of the formula, wherein the variables are defined in the specification, which bind to somatostatin receptors and block Na channels.

Description

1236477 A7 B7 五、發明説明（1 ) 發明之背景 本發明係針對具有式（I)與式（II)之化合物以及包含有 該等選擇性地結合至生長激素釋放抑制因子（somatostatin) 受體亞型的化合物之組成物，以及該等化合物用於治療由 生長激素釋放抑制因子受體亞型所調控之疾病的用途。生 長激素釋放抑制因子（somatostatin，生長激素釋放抑制因 子，SRIF)，一種十四肽激素，通常分離自牛的下視丘 (hypothalami)(Brazeau, P. et al.5 Science 179, 77-79, 1973) 已被顯示對於許多不同激素（諸如催乳激素、升血糖激素、 胰島素、胃激素）之釋出具有一廣範圍之調節作用（Bloom， S.R. and Poidack，J.M·，Brit. Med. 295, 288-289, 1987)。此 外，已利用生長激素釋放抑制因子類似物於轉移性攝護腺 癌（Parmar，H. et al，Clin. Exp. Metastasis，10，3-11，1992) 以及數種其他人類之神經内分泌性贅生物（Anthony，L. et al，Acta Oncol·，32，217-223，1993)上獲得抗增殖性質 (Reichlin，S.，N. Engl. J. Med. 309, 1495-1501，1983)。生長 激素釋放抑制因子透過胺基肽酶與羧基肽酶之代謝會導致 一短期間之作用。 生長激素釋放抑制因子係經由膜結合的受體而被調 節之。其生理功能之多相性引起了要鑑定胜肽類似物在生 長激素釋放抑制因子受體的結構-活性關係之研究，這造成 五種受體亞型之發現（Yamada，et al，Proc. Natl. Acad. Sci. U.S.A， 89， 251-255, 1992; Raynor, K. et al5 Mol.1236477 A7 B7 V. Description of the invention (1) Background of the invention The present invention is directed to compounds having formula (I) and formula (II) and compounds containing these selective binding to somatostatin receptor subunits. Compositions of compounds of the type I, and the use of these compounds for the treatment of diseases regulated by the growth hormone release inhibitor receptor subtype. Somatostatin (Somatostatin, SRIF), a tetradecapeptide hormone, usually isolated from the hypothalamus of cattle (Brazeau, P. et al. 5 Science 179, 77-79, 1973) has been shown to have a wide range of regulatory effects on the release of many different hormones (such as prolactin, glycemic hormone, insulin, stomach hormones) (Bloom, SR and Poidack, JM., Brit. Med. 295, 288 -289, 1987). In addition, growth hormone release inhibiting factor analogs have been used in metastatic prostate cancer (Parmar, H. et al, Clin. Exp. Metastasis, 10, 3-11, 1992) and several other human neuroendocrine neoplasms Antiproliferative properties were obtained on an organism (Anthony, L. et al, Acta Oncol., 32, 217-223, 1993) (Reichlin, S., N. Engl. J. Med. 309, 1495-1501, 1983). Metabolism of somatotropin release inhibitors through aminopeptidase and carboxypeptidase results in a short-term effect. Growth hormone release inhibitors are regulated via membrane-bound receptors. The heterogeneity of its physiological functions has led to studies to identify the structure-activity relationship of peptide analogues at the growth hormone release inhibitory factor receptor, which has led to the discovery of five receptor subtypes (Yamada, et al, Proc. Natl. Acad. Sci. USA, 89, 251-255, 1992; Raynor, K. et al5 Mol.

Phannacol·，44, 3 8 5-3 92, 1993)。此等受體之功能性角色被 -4- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 『裝— 訂· 1236477 A7 -------— 67 _ 五、發明説明（2 ) ^ — - 大量地研九t胃不同形式的生長激素釋放抑制因子亞型 之結合已與下列病狀和/或疾病之治療相關聯。第2與$型之 活化與生長激素（GH)抑制作用有關聯，特別是〇11分泌性腺 瘤[肢端肥大症（ACromegaly)]與促甲狀腺激素（TSH)分泌性 腺瘤。第2型但非第5型之活化與治療催乳激素分泌性腺瘤 有關聯。其他與生長激素釋放抑制因子亞型之活化有關聯 的病徵有：再狹窄，胰島素和/或升血糖激素之抑制且特別 是糖尿病，高血脂質症，胰島素不敏性，χ症候群，血管 病，增殖性視網膜病，dawn phenomenon與腎病，胃酸分 泌之抑制且特別是消化性潰瘍，腸與皮膚的 (enterocutaneous)以及胰與皮膚的（pancreatic〇cutan⑶別） 瘻管，刺激性腸症候群，傾倒症候群（Dumping syndr〇me)， 水瀉症候群，後天免疫缺乏症候群（AIDS)相關的腹瀉，化 學治療誘發的腹瀉，急性或慢性胰炎以及胃腸激素分泌性 腫瘤；癌症（諸如肝細胞瘤）之治療；血管發生之抑制，發 乂性疾病（諸如關節炎）之治療；慢性同種異體移植排斥； 血管成形術；防止移植物血管與胃腸出血。生長激素釋放 抑制因子同效劑亦可被使用於降低一病人之體重。 在藥物研究中，一個關鍵要點是發展出高效力且具選 擇性之藥物分子。近來對於非胜肽結構之研究（Hirschmann， R.etal，J.Am.Chem.Soc.ll5，12550-12568，1993·Phannacol., 44, 3 8 5-3 92, 1993). The functional role of these receptors is -4- This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling this page) "Packing-Order · 1236477 A7- -------- 67 _ V. Description of the invention (2) ^ —-A large number of studies have been made on the combination of different types of growth hormone release inhibitory factor subtypes in the stomach and have been associated with the treatment of the following conditions and / or diseases . Type 2 and $ activation are associated with growth hormone (GH) inhibitory effects, especially 011 secretory adenomas [ACromegaly] and thyroid-stimulating hormone (TSH) secretive adenomas. Activation of type 2 but not type 5 is associated with the treatment of prolactin-secreting adenomas. Other symptoms associated with the activation of growth hormone release inhibitor subtypes are: restenosis, inhibition of insulin and / or glycemic hormones and in particular diabetes, hyperlipidemia, insulin insensitivity, χ syndrome, vascular disease, Proliferative retinopathy, dawn phenomenon and kidney disease, inhibition of gastric acid secretion and especially peptic ulcer, enterocutaneous and pancreatic ocutan (fistula) fistula, irritating bowel syndrome, dumping syndrome syndromme), Watery Diarrhea Syndrome, Acquired Immune Deficiency Syndrome (AIDS) -related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, and gastrointestinal hormone-secreting tumors; treatment of cancers such as hepatocellular carcinoma; angiogenesis Inhibition, treatment of cyanotic diseases such as arthritis; chronic allograft rejection; angioplasty; prevention of graft vessel and gastrointestinal bleeding. Growth hormone release inhibitor synergists can also be used to reduce a patient's weight. A key point in drug research is the development of highly potent and selective drug molecules. Recent studies on the structure of non-peptides (Hirschmann, R. etal, J. Am. Chem. Soc. Ll5, 12550-12568, 1993.

Papageorgiou, C. and Borer, X., Bioorg. Med. Chem. Lett. 6, 267-272，1996)描述了具有低生長激素釋放抑制因子受 體親和性之化合物。 本紙張尺度適用中國國家標準（〇iS) A4規格（210X297公釐） --------------------裝----- (請先閲讀背面之注意事項再填窝本頁) 訂- 0, 1236477 A7 ______B7_ 五、發明説明（31 ~~' 再者，具有式（I)與式（II)之化合物係為鈉通道阻斷 劑，而因此展現出有用的藥理性質，特別是在神經病變性 疼痛（neuropathic pain)之緩解上的實用性。神經病變性疼 痛可被描述為與周圍或中樞神經系統之損害或永久性變質 有關聯之疼痛。神經病變性疼痛之臨床現象包含灼熱或電 震之感覺、身體扭曲之感覺、allodynia與感覺過敏 (hyperpathia) 〇 鈉通道阻斷劑已被報導在各種疾病狀態之治療上係 有效的。其等特別可用作為局部麻醉劑以及用於心律不整 之治療。多年前曾有人報導納通道阻斷劑可功用於治療疼 痛，包括神經病變性疼痛，參照，例如Tanelian ei a/.，Pah 4(2)，75-80,（1995)。有證據顯示鈉通道阻斷劑選 擇性地抑制受損神經之異位性神經熱（ect〇pic neural firing)，而此係經由被認為可用於舒緩疼痛之機制。但是， 就已知的鈉通道阻斷劑[例如胺甲醯氮革 (carbamazepine)、二苯基乙内醯脲鈉（phenyt〇in)、利度卡 因鹽酸鹽（lidocaine)、慢斯力丁（mexiletine)等等]所進行之 研究顯示出，此等試劑在中度劑量位準下對於神經病變性 疼痛病狀之治療不是非常有效，且即令在這些中度劑量位 準下，其等與許多非所欲副作用有關聯，諸如眩暈、嗔心、 嗜眠、震顫、含糊言語等等。臨床前的證據證實，鈉通道 阻斷劑選擇性地抑制受損的周圍與中樞神經元内之不正常 異位性神經熱，而此係經由被認為可用於舒緩疼痛之機 制。與此相一致的，已顯示鈉通道蓄積於位在軸索的損害 -6- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） I---— — — — — — — — — — — — — — —--— IE — (請先閱讀背面之注意事項再填寫本頁) 、可 参- 1236477 A7 -~~---ϋ___ 五、發明説明（4 ) " 位置處的周圍神經内。（Devor et al，； 1993, 132, 1976-1992)。因此，鈉通道藉由一受損神經之表現或分布 位準上之改變，從而對於與此種外傷相關聯的疼痛之病理 生理學具有-主要之影響。使用納通道調節劑（例如抗驚厥 劑、局部麻醉劑）來治療神經病變性疼痛之相當成功，可支 持此觀心。然而，疼痛舒緩通常同時會伴隨著許多不利 現象和/或有效性之限制，而限制了此等藥物之耐受性。可 以看出，對於一用於神經病變性疼痛之治療係為有效但具 較少之副作用的口服有效的試劑，仍然存在有一需要。 本發明之另一方面是有關於一種具有式⑴與式（π)之 化合物在一對於鈉通道阻斷劑有反應的哺乳動物之神經病 變性疼痛病狀之治療上的用途，該等病狀包括：周圍神經 病變，諸如三又神經痛、治療後神經痛、神經根病，以及 轉移性浸潤、痛性肥胖病與燒傷後發生的神經病變；以及 在中風、視丘損害與多發性硬化症後之中樞疼痛病狀，此 係藉由對該哺乳動物投藥以一治療有效量之一種具有式⑴ 與式（II)之化合物來達成。 於是’本發明之化合物被指明係要用於治療任一種在 病因學上涉及到麩胺酸鹽釋出之病理學、疾病或臨床病 狀’此等包括：精神病學疾病[諸如精神分裂症、抑鬱、焦 慮、恐慌發作、注意力不足與辨識障礙（cognitive disorders)、社會退縮（s〇cial withdrawal)]，激素病狀[過量 的GH ’例如在糖尿病、血管病與肢端肥大症之治療上，或 促黃體生成素（LH)分泌，例如攝護腺肥大症、停經症候群、 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂丨 麟- 1236477 A7 ____B7 1、發明説明（5 ) — 一 ' 抑壓下之皮質脂酮分泌]，代謝引起的腦損害[血糖過少 症、非酮性血甘油脂過多症（甘胺酸腦病）]、亞硫酸鹽氧化 酶不足、與肝衰竭有關的肝性腦病]，嘔吐，痙攣，癲痛、 耳鳴，疼痛（例如癌症疼痛、關節炎）與藥物[酒精，鴉片劑， 包括具鴉片劑般作用之合成物，例如陪替丁（pethidine)、 美舍東（methadone)專等，古柯驗，安非他命，巴比特鹽與 其他鎮靜劑’本並一氣二稀柒圜類（benzodiazepines)]，濫 用與戒斷。 更甚者’本發明之一化合物被指明要用於治療任一種 涉及神經元損害之病理學，例如神經退化性疾病（諸如阿滋 海默氏症、杭丁頓氏症或帕金森氏症），病毒[包含人類免 疫缺乏病毒（HIV)]誘發的神經退化，肌萎縮性脊縫側索硬 化症（ALS)，核上的靡瘓（SUpra_nuciear paiSy)，下撖欖體橋 腦小腦萎縮（OPCA)，以及環境與外源性神經毒素之作用。 發明之概要説明 在一方面，本發明係針對具有式⑴之化合物，該具有 式⑴之化合物之消旋-非對映異構體混合物與光學異構 物’此等之藥學上可接受的鹽類或前驅藥，或該前驅藥之 藥學上可接受的鹽類： -----------•裝........... (請先閱讀背面之注意事項再填寫本頁) 、?!1 0,Papageorgiou, C. and Borer, X., Bioorg. Med. Chem. Lett. 6, 267-272, 1996) describe compounds having low affinity for the growth hormone release inhibitory factor receptor. This paper size applies the Chinese National Standard (〇iS) A4 specification (210X297 mm) -------------------- Packing ----- (Please read the Note for refilling this page) Order-0, 1236477 A7 ______B7_ V. Description of the invention (31 ~~ 'Furthermore, compounds with formula (I) and formula (II) are sodium channel blockers, and therefore show It has useful pharmacological properties, especially in the relief of neuropathic pain. Neuropathic pain can be described as pain associated with damage or permanent deterioration of the peripheral or central nervous system. Neuropathic pain Clinical phenomena include feeling of burning or electric shock, feeling of physical distortion, allodynia and hyperpathia. Sodium channel blockers have been reported to be effective in the treatment of various disease states. They are particularly useful as local anesthetics And for the treatment of arrhythmias. It has been reported many years ago that nanochannel blockers can be used to treat pain, including neuropathic pain. For example, Tanelian ei a /., Pah 4 (2), 75-80, (1995 ). There is evidence showing sodium Channel blockers selectively inhibit ectopic neural firing of damaged nerves, and this is via a mechanism that is thought to be useful for pain relief. However, known sodium channel blockers [ For example, studies carried out by carbamazepine, phenytoin, lidocaine hydrochloride (lidocaine, mexiletine, etc.) show that However, these agents are not very effective in the treatment of neuropathic pain conditions at moderate dose levels, and even at these moderate dose levels, they are associated with many undesired side effects such as dizziness, dysentery Heart, lethargy, tremor, ambiguous speech, etc. Preclinical evidence confirms that sodium channel blockers selectively inhibit abnormal ectopic neural heat in damaged peripheral and central neurons, which is thought to be via It can be used for the mechanism of relieving pain. Consistent with this, it has been shown that the sodium channel accumulates in the axonal damage -6- This paper size applies to China National Standard (CNS) A4 (210X297 mm) I ---- — — — — — — — — — — — — — — — IE — (Please read the notes on the back before filling out this page), you can refer to-1236477 A7-~~ --- ϋ ___ V. Description of the invention (4) " (Devor et al, 1993, 132, 1976-1992). Therefore, the sodium channel changes in the expression or distribution level of a damaged nerve, thereby reducing the pain associated with such trauma. The pathophysiology has-a major impact. The use of nanochannel modulators (eg, anticonvulsants, local anesthetics) to treat neuropathic pain has been quite successful and can support this mindset. However, pain relief is often accompanied by many adverse phenomena and / or limitations of effectiveness, which limit the tolerance of these drugs. It can be seen that there is still a need for an orally effective agent that is effective but has fewer side effects for the treatment of neuropathic pain. Another aspect of the present invention relates to the use of a compound of formula (I) and formula (π) for the treatment of a neuropathic pain condition in a mammal that responds to a sodium channel blocker. The conditions include : Peripheral neuropathy, such as triple neuralgia, post-treatment neuralgia, radiculopathy, and neuropathy that occurs after metastatic infiltration, painful obesity, and burns; and after stroke, mastopathy, and multiple sclerosis Central pain conditions are achieved by administering to a mammal a therapeutically effective amount of a compound having formula (II) and formula (II). Thus, 'the compounds of the present invention are indicated for the treatment of any pathological, disease or clinical condition that is etiologically involved in the release of glutamate'. These include: psychiatric diseases [such as schizophrenia, Depression, anxiety, panic attacks, lack of attention and cognitive disorders, social withdrawal], hormonal conditions [excessive GH 'for example in the treatment of diabetes, vascular disease and acromegaly , Or luteinizing hormone (LH) secretion, such as prostate hypertrophy, menopausal syndrome, this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page ) Order 丨 Lin- 1236477 A7 ____B7 1. Description of the invention (5)-a 'cortisol secretion under depression], brain damage caused by metabolism [hypoglycemia, non-ketoglycemia (glycine) Encephalopathy)], deficiency of sulfite oxidase, hepatic encephalopathy associated with liver failure], vomiting, convulsions, epilepsy, tinnitus, pain (such as cancer pain, arthritis) and drugs [alcohol, Tablets, including compounds with opiate-like effects, such as pethidine, methadon, coca test, amphetamine, babbit salt and other sedatives. Benzodiazepines], abuse and withdrawal. What's more, one of the compounds of the present invention is indicated for the treatment of any pathology involving neuronal damage, such as neurodegenerative diseases (such as Alzheimer's disease, Huntington's disease, or Parkinson's disease) , Virus [including human immunodeficiency virus (HIV)]-induced neurodegeneration, amyotrophic lateral sclerosis (ALS), nuclear paralysis (SUpra_nuciear paiSy), mandibular acroponin cerebellar atrophy (OPCA) ), And the role of the environment and exogenous neurotoxins. SUMMARY OF THE INVENTION In one aspect, the present invention is directed to a compound of formula XI, a racemic-diastereomeric mixture of the compound of formula IX and optical isomers of such pharmaceutically acceptable salts Or prodrug, or the pharmaceutically acceptable salts of the prodrug: ----------- • pack ......... (Please read the precautions on the back first Fill out this page again),?! 1 0,

本紙張尺度適用中咖家標準（CNS) A4規格⑵〇χ297 1236477This paper size is applicable to CNS A4 specification 〇χ297 1236477

(C0-C6)(C0-C6)

A7 五、發明説明 (I) 其中 表示一個任擇的鍵結 X為N或N-R4,其中當兩個任擇的鍵結存在時又為^，而 當兩個任擇的鍵結不存在時X為N-R4 ; R 為 Η、-(CUc^OHCDm-Z1、_(cjj2) ζι、 -(CH2)m-0-Z 或（C〇-C6)烧基-C(0)-NH-(CH2)m-Z3 · z係為一個選自下列群中之經任擇取代的部分： (C^-Cu)烷基、苯並[b]噻吩、苯基、萘基、苯並[b]呋喃基、 噻吩、異噁唑基、吲哚基、 R 係為（CVCu)烷基、（c〇-C6)烷基-(:(0)-0-2 = 烧基-C(〇)-NH-(CH2)m-Z3或任擇取代的苯基； Z5係為Η、（CVC12)烷基或（CH2)m-芳基； 3 y z係為胺基、（CVCu)烷基胺基、ν，Ν·二-(CVC12)烷基 胺基、-NH-C(0)-0-(CH2)m苯基、-丽-C(〇)-〇-(CH2)m-(Ci-C6) 烧基或一個選自下列群中之經任擇取代的部分··咪唑基、 °比σ疋基與嗎琳基、σ底唆基、σ辰嗔基、比唑琳基、呋喃基與 噻吩； R3係為Η ; R4係為 Η、-CbYyNCXi2)、C(=0)X2或 X2 ; y係為〇或s ; -9- 本紙張尺度適用中國國家標準（CNS) A4規格（2K)X297公釐〉 1236477 A7 B7 五、發明説明 X2 係為-(CHJm-YLx3; (請先閲讀背面之注意事項再填寫本頁) X3係為Η或一個選自下列群中之經任擇取代的部分： (C!-C12)烷基、（C3-C8)環烷基、（CVCu)烷氧基、芳氧基、 (CVC12)烷基胺基、n，N-二-(Ci-Cu)烷基胺基、-CH-二 _(Ci-C12)烧氧基或苯基； R5係為（C「C12)烷氧基-(CH2)m_YL(CH2)m·苯基-(X1、、 (C3-C12)環烷基、-(CH2)m-S-(CVC12)烷基、（CVCu)烷基 ^^-((^-(^⑴烷基〜-^^‘兴^^“炔基或一個選自下列 群中之經任擇取代的部分：苯基、吱喃基、嘆吩、U比17各基、 ίίΧ〉 吡啶基以及^^0 ; Y1係為0、S、NH或一個鍵結； R6係為Η或S02-苯基； R7係為Η、被任擇地取代以烷氧基或二烷基胺基之烷 基； 麟- 其中一個經任擇取代的部分或苯基被任擇地取代以 一或多個各自選自下列群中之取代基：C卜F、Br、I、CF3、 N02、OH、S02NH2、CN、N3、_〇CF3、（Ci-Cu)烷氧基、 -(CH2)m-苯基-(X1)，-NH-CCKCVCd烷基、-S-苯基-(Xl、 -0_(CH2)m-苯基-(X1),、-(CHdm-CXCO-CHCVCO 烷基、 -(CH2)m-C(0)-(C1-C6)烷基、-0-(CH2)m-NH2 、 -O-CCHOm-NH-CC!·^)烷基、-〇-(CH2)m-N-二-[(CVC6)烷基] 以及-(C〇-C12)烷基-(Χ^ ; -10· 本紙張尺度適用中國國家標準（CNS) Α4規格（210X297公爱） 1236477 五、發明説明 X在每次出現係各自為選自於下列群中：氫、C1、ρ、 Br、I、N02、OH、-Cf3、_〇CF3、（(VCi2)烧基、（(VCi2) 院氧基、-S-(CVC6)烧基、-(CH2)nr 胺基、（CH2)m-NH-(Ci-C6) 烧基、-(CH2)m-N-二-[(Cl-C6)烷基]、-(CH2)m-苯基以及 (CH2)m_NH_(C3-C6)環烷基； m在母—人出現係各自為〇或一個由1至6之整數；以及 η在母久出現係各自為一個由1至5之整數。 一個較佳之具有式⑴之化合物係為其中X為ΝΗ ; R1為 Η ; R2為-CH(CH3)2-C〇-NH-(CH2)mZ3，其中 R2之定義中的 m 係為1、2或3 ; z3係為咪嗤基、吡啶基、嗎啉代或N，N_二-乙胺基； R係為丙基、正丁基、正戊基、_(CH2)-〇-(CH2)-苯基、 2-硝基 _3-0Me-苯基、p-t-Bu-苯基、m-〇Me-苯基、o-〇Me- 苯基、p-硝基-苯基、_(CH2)2-S-Me、環己基、m_Br-苯基、 P-S-Me-苯基、ρ_Ν，Ν·二曱基胺基-苯基、m_甲基·苯基或 • 0A7 V. Description of the invention (I) where an optional bond X is N or N-R4, where ^ is present when two optional bonds are present, and when two optional bonds are not present When X is N-R4; R is Η,-(CUc ^ OHCDm-Z1, _ (cjj2) ζι,-(CH2) m-0-Z or (C〇-C6) alkyl-C (0) -NH -(CH2) m-Z3 · z is an optionally substituted moiety selected from the group consisting of (C ^ -Cu) alkyl, benzo [b] thiophene, phenyl, naphthyl, benzo [ b] Furyl, thiophene, isoxazolyl, indolyl, R is (CVCu) alkyl, (c0-C6) alkyl-(:( 0) -0-2 = alkyl-C (〇 ) -NH- (CH2) m-Z3 or optionally substituted phenyl; Z5 is fluorene, (CVC12) alkyl or (CH2) m-aryl; 3 yz is amine, (CVCu) alkylamine Group, ν, N · di- (CVC12) alkylamino group, -NH-C (0) -0- (CH2) mphenyl group, -Li-C (〇) -〇- (CH2) m- (Ci -C6) alkynyl or an optionally substituted moiety selected from the group consisting of imidazolyl, ° ratio σ 疋 and morphinyl, σ base, σ cinyl, bisazoline, furan And thiophene; R3 is Η; R4 is Η, -CbYyNCXi2), C (= 0) X2 or X2; y is 0 or s; -9- this paper Applicable to China National Standard (CNS) A4 specification (2K) X297 mm> 1236477 A7 B7 5. Description of the invention X2 is-(CHJm-YLx3; (Please read the precautions on the back before filling this page) X3 is Η Or an optionally substituted moiety selected from the group consisting of (C! -C12) alkyl, (C3-C8) cycloalkyl, (CVCu) alkoxy, aryloxy, (CVC12) alkylamine Group, n, N-di- (Ci-Cu) alkylamino group, -CH-di- (Ci-C12) alkyloxy or phenyl group; R5 is (C "C12) alkoxy- (CH2) m_YL (CH2) m · phenyl- (X1 ,, (C3-C12) cycloalkyl,-(CH2) mS- (CVC12) alkyl, (CVCu) alkyl ^^-((^-(^ fluorane Group ~-^^ '兴 ^^ "alkynyl or an optionally substituted moiety selected from the group consisting of phenyl, sulfanyl, thiophene, each group of U than 17, pyridyl and ^^ 0; Y1 is 0, S, NH or a bond; R6 is fluorene or S02-phenyl; R7 is fluorene, an alkyl group optionally substituted with an alkoxy or dialkylamino group; lin -One of the optionally substituted moieties or phenyl groups is optionally substituted with one or more substituents each selected from the group: C, F, Br, I, CF3, N02, OH, S 02NH2, CN, N3, _〇CF3, (Ci-Cu) alkoxy,-(CH2) m-phenyl- (X1), -NH-CCKCVCd alkyl, -S-phenyl- (Xl, -0_ (CH2) m-phenyl- (X1),-(CHdm-CXCO-CHCVCO alkyl,-(CH2) mC (0)-(C1-C6) alkyl, -0- (CH2) m-NH2, -O-CCHOm-NH-CC! ^) Alkyl, -0- (CH2) mN-di-[(CVC6) alkyl], and-(C〇-C12) alkyl- (χ ^; -10 · This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 public love) 1236477 V. Description of the invention In each occurrence, X is selected from the following groups: hydrogen, C1, ρ, Br, I, N02, OH , -Cf3, _〇CF3, ((VCi2) alkyl group, ((VCi2) alkyl group, -S- (CVC6) alkyl group,-(CH2) nr amino group, (CH2) m-NH- (Ci- C6) alkyl,-(CH2) mN-di-[(Cl-C6) alkyl],-(CH2) m-phenyl, and (CH2) m_NH_ (C3-C6) cycloalkyl; m is in parent-human The occurrences are each 0 or an integer from 1 to 6; and the occurrence of η in the mother is each an integer from 1 to 5. A preferred compound having formula ⑴ is where X is NΗ; R1 is Η; R2 is -CH (CH3) 2-C0-NH- (CH2) mZ3, where m in the definition of R2 is 1, 2 Or 3; z3 is imidino, pyridyl, morpholino or N, N-di-ethylamino; R is propyl, n-butyl, n-pentyl, _ (CH2) -〇- (CH2 ) -Phenyl, 2-nitro-3-0Me-phenyl, pt-Bu-phenyl, m-〇Me-phenyl, o-〇Me-phenyl, p-nitro-phenyl, _ ( CH2) 2-S-Me, cyclohexyl, m_Br-phenyl, PS-Me-phenyl, ρ_N, N · diamidinoamino-phenyl, m_methyl · phenyl, or • 0

〇 R6係為Η ;以及R7係為Η。 另一個較佳之具有式（I)之化合物係為其中乂為1^11 ; Ri 為Η ; R2為苯基；R係為丙基、正丁基、正戊基、正庚基、新戊基、環丙 基、環己基、-(CH2)2-S-Me、苯基、-(CH2)-〇-(CH2)-苯基、 2-硝基-3-OMe-苯基、p-t-Bu-苯基、〇-〇Me-苯基、m-〇Me- 本基、p-OMe-苯基、3,4,5-三-OMe-苯基、p-丁氧基-苯基、 -11- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公爱） (請先閲讀背面之注意事項再填寫本頁} £-〇 R6 is Η; and R7 is Η. Another preferred compound having formula (I) is wherein 乂 is 1 ^ 11; Ri is Η; R2 is phenyl; R is propyl, n-butyl, n-pentyl, n-heptyl, neopentyl , Cyclopropyl, cyclohexyl,-(CH2) 2-S-Me, phenyl,-(CH2) -〇- (CH2) -phenyl, 2-nitro-3-OMe-phenyl, pt-Bu -Phenyl, 〇-〇Me-phenyl, m-〇Me-benzyl, p-OMe-phenyl, 3,4,5-tri-OMe-phenyl, p-butoxy-phenyl,- 11- This paper size applies to China National Standard (CNS) A4 (210X297 public love) (Please read the precautions on the back before filling this page} £-

•、盯I 麟- 1236477 A7 ____ B7_ 五、發明説明（9 ) 3 -乙氧基-4-甲氧基-苯基、〇 -石肖基-苯基、p_硝基-苯基、 p-OCF3-苯基、〇-〇CF3-苯基、3-F-4-Ome-苯基、o-F-苯基、 o-Br-苯基、m-Br-苯基、p-Br-苯基、2,4-二-C1-苯基、3,4· 二-C1-苯基、p-(3-(N，N-二曱基胺基）丙氧基）苯基、 -(CH2)2-S-Me、環己基、p-(Me-CO-NH-)-苯基、p-t-Bu-苯 基、p-OH-苯基、p-(S-Me)-苯基、p-(_S-t-Bu)·苯基、p-N，N-一甲基胺基-苯基、m-曱基-苯基、3-OH-4-OMe -苯基、ρ_ 卜广〉N。2 丫丫。〉 苯基-苯基、^^0 或 ； R6係為Η ;以及R7係為Η。 另一個較佳之具有式⑴之化合物係為其中X為ΝΗ ; R1 為Η ; R2為ρ-OMe·苯基或ρ-硝基-苯基； R5係為正丁基、正戊基、正己基、異丁基、環己基、 -(CH2)2-S-Me、苯基、m-OMe-苯基、2_硝基-3-OMe-苯基、 ρ-硝基·苯基、p-t-Bu-苯基、ρ-硫曱基-苯基、m-Br-苯基、 2-OMe-4-二曱基胺基-苯基、P-(3-(n，N-二曱基胺基）丙氧基) 苯基、ρ-二甲基胺基-苯基、3-硝基-4-C1-苯基、 &。〉 -(CH2)-0-(CH2)_ 苯基或、^^0 ; R6係為Η ;以及R7係為Η。 在另一方面，本發明係針對具有式（Π)之化合物，該具 有式（II)之化合物之消旋-非對映異構體混合物與光學異構 -12- 本紙張尺度適用中國國家標準（CNS) Α4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) .、?τ— 1236477 A7 ----------B7___ 五、發明説明（10 ) 物’此等之藥學上可接受的鹽類或前驅藥，或該前驅藥之 藥學上可接受的鹽類： R2•, I Lin-1236477 A7 ____ B7_ V. Description of the invention (9) 3-ethoxy-4-methoxy-phenyl, 0-stone-synyl-phenyl, p_nitro-phenyl, p-OCF3 -Phenyl, 〇-〇CF3-phenyl, 3-F-4-Ome-phenyl, oF-phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, 2 , 4-di-C1-phenyl, 3,4 · di-C1-phenyl, p- (3- (N, N-diamidoamino) propoxy) phenyl,-(CH2) 2- S-Me, cyclohexyl, p- (Me-CO-NH-)-phenyl, pt-Bu-phenyl, p-OH-phenyl, p- (S-Me) -phenyl, p-(_ S -t-Bu) · phenyl, pN, N-monomethylamino-phenyl, m-fluorenyl-phenyl, 3-OH-4-OMe-phenyl, ρ_Bu Guang> N. 2 Yaya. > Phenyl-phenyl, ^^ 0 or; R6 is fluorene; and R7 is fluorene. Another preferred compound having the formula 为 is wherein X is NΗ; R1 is Η; R2 is ρ-OMe · phenyl or ρ-nitro-phenyl; R5 is n-butyl, n-pentyl, n-hexyl , Isobutyl, cyclohexyl,-(CH2) 2-S-Me, phenyl, m-OMe-phenyl, 2-nitro-3-OMe-phenyl, ρ-nitro · phenyl, pt- Bu-phenyl, ρ-thiofluorenyl-phenyl, m-Br-phenyl, 2-OMe-4-difluorenylamino-phenyl, P- (3- (n, N-difluorenylamine) Group) propoxy) phenyl, p-dimethylamino-phenyl, 3-nitro-4-C1-phenyl, &. 〉-(CH2) -0- (CH2) _phenyl or ^^ 0; R6 is Η; and R7 is Η. In another aspect, the present invention is directed to a compound having the formula (Π), and the racemic-diastereomeric mixture and optical isomerization of the compound having the formula (II) -12- This paper applies Chinese national standards (CNS) Α4 specification (210X297 mm) (Please read the notes on the back before filling out this page).,? Τ-1236477 A7 ---------- B7___ V. Description of the invention (10) These pharmaceutically acceptable salts or prodrugs, or the pharmaceutically acceptable salts of the prodrug: R2

(Π) 其中 ........表示一個任擇的鍵結； J1係為N-R6或S ; J2係為 N-R1、0 或 S ; X係為N或N-R4，其中當兩個任擇的鍵結存在時X為n， 而當該等任擇的鍵結不存在時X為N-R4 ; Ri 為 Η 、-(CH2)m-C(0)-(CH2)m-Z1 、'(CU2)m^Zl 、 -(CHJm-O-Z1 或（C0-C6)烷基-C(0)-NH-(CH2)m-Z3 ; z1係為一個選自下列群中之經任擇取代的部分： (Ci-Ci2)烧基、苯並[b]嗔吩、苯基、萘基、苯並[b]吱喃基、(Π) where ... indicates an optional bond; J1 is N-R6 or S; J2 is N-R1, 0 or S; X is N or N-R4, where X is n when two optional bonds are present, and X is N-R4 when the optional bonds are not present; Ri is Η,-(CH2) mC (0)-(CH2) m- Z1, '(CU2) m ^ Zl,-(CHJm-O-Z1 or (C0-C6) alkyl-C (0) -NH- (CH2) m-Z3; z1 is a member selected from the group Optionally substituted moieties: (Ci-Ci2) alkyl, benzo [b] pyrene, phenyl, naphthyl, benzo [b] anyl,

(請先閱讀背面之注意事項再填寫本頁) 裝· •訂— 0, R2係為（Ci-Cu)烷基、（C〇_C6)烷基-C(0)-0-Z5、（C(rC6) 烷基-C(0)-NH-(CH2)m-Z3或任擇取代的苯基； -13- 本紙張尺度適用中國國家標準（CNS) A4規格（2】〇X297公釐） 1236477 A7 ___ _B7_ 五、發明説明（U ) Z5係為Η、（CVCu)烷基或（CH2)m-芳基； Z3係為胺基、（Ci-C!】）烧基胺基、N，N-二-(C^Cu)统基 胺 基 、 -NH-C(0)-0-(CH2)m- 苯 基 、 -NH-C(0)-0-(0112)^((^-(^6)烧基或一個選自下列群中之經 任擇取代的部分：苯基、咪唑基、吡啶基與嗎琳基、旅唆 基、σ底嗔基、ϋ比嗤琳基、吱喃基與嗔吩； R3係為Η、（Ci-C6)烧基、或經任擇取代的苯基； R4係為 Η、-CbYhNCXiX2)、C(=0)X2 或 X2 ; Y係為0或S ; X2係為 Η或-(CHJm-Y^X3; X3係為Η或一個選自下列群中之經任擇取代的部分： (cvcu)烷基、（c3-c8)環烷基、（cvcy烷氧基、芳氧基、 (Ci-c12)烷基胺基、N，N•二 _(Cl_Cl2)烷基胺基、-CH_: -(Ci-C12)烧氧基或苯基； R5與R8各自選自於下列群中：Η、（Ci-Cu)烷基、 _(CH2)m-Yi-(CH2)m•苯基-(χ1)η、（C3-Ci2)環烷基、（(VCi2) 環炔基、-(CHdm-SJCVCu)烷基、（CVCu)烷基-S-SJCVD 烧基、-(CDm^Ci-Cu)快基以及一個選自下列群中之經任 擇取代的部分：苯基、吱喃基、嗔吩、σ比洛基、0比咬基以 _^(C;_C4)烧基一+ \ 及 0， 但有條件是R5與R8不得同時為Η ; _ -14- 本紙張尺度顏(⑽Μ規格（2歌Μ (請先閲讀背面之注意事項再填寫本頁) •訂· 參 1236477 A7 五、發明説明 或V與R8和其等所連接之碳原子一起形成★yN-A-B-f(Please read the precautions on the back before filling out this page) Assembly · • Order — 0, R2 is (Ci-Cu) alkyl, (C〇_C6) alkyl-C (0) -0-Z5, ( C (rC6) alkyl-C (0) -NH- (CH2) m-Z3 or optionally substituted phenyl; -13- This paper size applies to China National Standard (CNS) A4 specifications (2) × 297 mm ) 1236477 A7 ___ _B7_ 5. Description of the invention (U) Z5 is fluorene, (CVCu) alkyl or (CH2) m-aryl; Z3 is amine, (Ci-C!]) Alkylamino, N , N-di- (C ^ Cu) ylamino, -NH-C (0) -0- (CH2) m-phenyl, -NH-C (0) -0- (0112) ^ ((^ -(^ 6) alkenyl or an optionally substituted moiety selected from the group consisting of phenyl, imidazolyl, pyridyl and morphinyl, bridging group, stilbyl group, pyrimidine group, Cranyl and phenol; R3 is fluorene, (Ci-C6) alkyl, or optionally substituted phenyl; R4 is fluorene, -CbYhNCXiX2), C (= 0) X2 or X2; Y is 0 or S; X2 is Η or-(CHJm-Y ^ X3; X3 is Η or an optionally substituted moiety selected from the group consisting of: (cvcu) alkyl, (c3-c8) cycloalkyl (Cvcy alkoxy, aryloxy, (Ci-c12) alkylamino, N, N • di _ (Cl_Cl2) alkylamino, -CH_:-(Ci-C12) alkyloxy or phenyl; R5 and R8 are each selected from the group consisting of: Η, (Ci-Cu) alkyl, _ (CH2) m-Yi- (CH2) m • phenyl- (χ1) η, (C3-Ci2) cycloalkyl, ((VCi2) cycloalkynyl,-(CHdm-SJCVCu) alkyl, (CVCu) alkyl-S -SJCVD thiol,-(CDm ^ Ci-Cu) quick radical, and an optionally substituted moiety selected from the group consisting of phenyl, succinyl, methylphene, stilbyl, _ ^ (C; _C4) Burning base + + and 0, but the condition is that R5 and R8 must not be Η at the same time; _ -14- The size of this paper (⑽Μ specifications (2 songs M (Please read the precautions on the back first) (Fill in this page again) • Order · See 1236477 A7 V. Description of the invention or V is formed with R8 and the carbon atoms connected to it yN-ABf

CO 螺狀（C4-C12)環烷基，或或\—^/ Y1係為0、S、NH或一個鍵結； A係為一個鍵結、-C0-、_C(0)0_、_c(〇)NH、_c(s)nh_ 或-S02-; 整 -— — — — — I1IIIIIIIIIII — I I _ I (請先閱讀背面之注意事項再填寫本頁) B係為一個鍵結或-(CH2)q-，其中q係為一個由i至6之 數； .、訂· J3係為Η、（q-C6)烷基、經任擇取代的苯基、經任擇取 代的雜芳基或N(R9R1G) ’其中R9與R"各自選自於下列群 中·（Cl-C6)烧基以及經任擇取代的苯基，或R9與R 10和其等 所連接之IL原子一起形成一個含有R9與rIG所連接之氣原 子的具有5至8個成員之環，其中該環的成員中之一者可任 擇地為一個氧原子或NR11，其中Rii為（Ci-c6)烷基、 烷基、-qco-i^vW2)、或經任 擇取代的-苯基-(C〇-C6)烧基，其中v1與V2各自選自於下列 群中：H^CVCu)烷基或經任擇取代的-苯基-(C(rC6)烷基； R6係為Η或S02-苯基； R7係為 Η、Cl、F、Br、I、CF3、N〇2、OH、S02NH2、 CN、N3、-〇CF3、（CVCu)烧氧基、-(CH2)m-苯基、 -NH-CO-(Ci-C6)院基、-S-(Ci-Ci2)烧基、_s_ 苯基-(X1)!^ -0-(CH2)m-苯基-(xbn、-(CH2)m-C(0)-CKCVC6)烷基、 -(CH2)m-C(0)-(C1-C6)烷 基、-0-(CH2)m-NH2 、 -15- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 A7 B7 13 五、發明説明、， -O-CCHJm-NiHCVC^)燒基、_〇_(CH2)m_N_>[(C 厂 C6)炫基] 以及-(c〇-c12)烷基-(x^ ; (請先閲讀背面之注意事項再填寫本頁) 其中一個經任擇取代的部分或苯基被任擇地取代以一 或多個各自選自下列群中之取代基·· Cl、F、Br、I、CF3、 N〇2、OH、S02NH2、CN、N3、-〇CF3、（cvc12)烧氧基、 -(CH2)m-笨基-(X1；^、-NH_c〇_(c广C6)烧基、各(Ci-Ci2)烷 基、-S-苯基-(Xbn 、 -〇_(CH2)『苯基彳χ1)η 、 -(CHJm-CCOhCKCVQ)烧基、_(CH2)m-C(0)_(Cl-C6)院基、 -0-(CH2)m->iH2、-〇-(CH2)nrNH-(Ci-C6)烷基、办（CH2)nrN_ 二·[(Ci-Cd烧基]以及-(Co-D烧基-(Χ^η ; X1在每次出現係各自為選自於下列群中：氫、cr、F、 Br、I、N02、OH、-CF3、-〇CF3、（CVCu)烷基、（CVCu) 烧氧基、-S-CCi-D烷基、_(CH2)m-胺基、-((:^-丽-⑹-⑸ 烧基、-(CH2)m-N-二-[(CVC6)烷基]、-(CH2)m-苯基以及 -(CH2)m_NH-(C3-C6)環烷基； m在母次出現係各自為〇或一個由1至6之整數；以及 η在每次出現係各自為一個由1至5之整數。 一個較佳之具有式（II)之化合物係為那些具有式（IIa) 者：CO Spiro (C4-C12) cycloalkyl, or \-^ / Y1 is 0, S, NH or a bond; A is a bond, -C0-, _C (0) 0_, _c ( 〇) NH, _c (s) nh_ or -S02-; integer--— — — — I1IIIIIIIIIII — II _ I (Please read the notes on the back before filling this page) B is a bond or-(CH2) q-, where q is a number from i to 6;., J3 is fluorene, (q-C6) alkyl, optionally substituted phenyl, optionally substituted heteroaryl, or N (R9R1G) 'wherein R9 and R " are each selected from the group consisting of (Cl-C6) alkyl and optionally substituted phenyl, or R9 and R 10 together with the IL atom to which they are attached form a group containing A ring having 5 to 8 members of the gas atom to which R9 and rIG are connected, wherein one of the members of the ring is optionally an oxygen atom or NR11, wherein Rii is (Ci-c6) alkyl, alkane Group, -qco-i ^ vW2), or optionally substituted -phenyl- (C0-C6) alkyl, wherein v1 and V2 are each selected from the group consisting of H ^ CVCu) alkyl or any Optionally substituted -phenyl- (C (rC6) alkyl); R6 is fluorene or S02-phenyl; R7 is fluorene, Cl, F, Br, I, CF3 N〇2, OH, S02NH2, CN, N3, -〇CF3, (CVCu) alkoxy,-(CH2) m-phenyl, -NH-CO- (Ci-C6) courtyard, -S- (Ci -Ci2) alkyl, _s_phenyl- (X1)! ^ -0- (CH2) m-phenyl- (xbn,-(CH2) mC (0) -CKCVC6) alkyl,-(CH2) mC (0 )-(C1-C6) alkyl, -0- (CH2) m-NH2, -15- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 1236477 A7 B7 13 V. Description of the invention, -O-CCHJm-NiHCVC ^) alkyl group, _〇_ (CH2) m_N_ > [(C Factory C6) Hexyl] and-(c〇-c12) alkyl- (x ^; (Please read the note on the back first Please fill in this page again) One of the optionally substituted moieties or phenyl groups is optionally substituted with one or more substituents each selected from the group Cl, F, Br, I, CF3, N. 2, OH, S02NH2, CN, N3, -〇CF3, (cvc12) alkoxy,-(CH2) m-benzyl- (X1; ^, -NH_c〇_ (c-C6)), each (Ci -Ci2) alkyl, -S-phenyl- (Xbn, -〇_ (CH2) 『phenyl 彳 χ1) η,-(CHJm-CCOhCKCVQ) alkyl, _ (CH2) mC (0) _ (Cl- C6) courtyard, -0- (CH2) m- > iH2, -0- (CH2) nrNH- (Ci-C6) alkyl, (CH2) nrN _ [[Ci-Cd alkyl], and- (Co-D -(Χ ^ η; X1 in each occurrence is selected from the group consisting of hydrogen, cr, F, Br, I, N02, OH, -CF3, -〇CF3, (CVCu) alkyl, CVCu) carboxy, -S-CCi-D alkyl, _ (CH2) m-amino,-((: ^-Li-⑹-fluorenyl),-(CH2) mN-di-[(CVC6) Alkyl],-(CH2) m-phenyl, and-(CH2) m_NH- (C3-C6) cycloalkyl; m in the parent and minor occurrences are each 0 or an integer from 1 to 6; and η in each Each occurrence is an integer from 1 to 5. A preferred compound having formula (II) is those having formula (IIa):

本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 五、發明説明（14 其中 R3係為Η或甲基； R4係為Η或甲基； R5係為Η、甲基、乙基、丁基、戊基或己基； R8係為乙基、丁基、戊基、己基或環己基； 或R5與R8與其等所連接之碳原子一起形成螺狀環己/〇〇. 基、螺狀環庚基、螺狀金剛烷基This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1236477 V. Description of the invention (14 where R3 is fluorene or methyl; R4 is fluorene or methyl; R5 is fluorene, methyl, B Group, butyl, pentyl or hexyl; R8 is ethyl, butyl, pentyl, hexyl or cyclohexyl; or R5 and R8 together with the carbon atom to which they are attached form a helical cyclohexyl / 〇〇. Group, Spiro-cycloheptyl, Spiro-adamantyl

S 或 Ν-Α-Β-/ 其中A係為一個鍵結或—C (0) 0 -，B係為一個鍵結、-C Η 2 _ 或-(CH2)2-; J3係為Η或苯基；以及 R 係為 Η、Me、F、Cl、ΟΗ、-0-甲基或 _〇-Ch2-苯基。 一個更佳之具有式（II)之化合物係為那些化合物，其 中： R、R4與R7各自為氫，R5與R8 一起形成 唑基係居於R-構形； 以及咪 R3、R4與R7各自為氫，R5與R8 —起形成00 咪唑基係居於R-構形； 以及 c請先閱讀背面之注意事項再填寫本頁) •訂丨 -17- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 A7S or Ν-Α-Β- / where A is a bond or -C (0) 0-, B is a bond, -C Η 2 _ or-(CH2) 2-; J3 is Η or Phenyl; and R is fluorene, Me, F, Cl, 0Η, -0-methyl, or -0-Ch2-phenyl. A more preferred compound system having formula (II) are those compounds, wherein: R, R4 and R7 are each hydrogen, R5 and R8 together form an azolyl group in the R-configuration; and R3, R4 and R7 are each hydrogen , R5 and R8 together form 00 imidazolyl system in the R-configuration; and c, please read the notes on the back before filling in this page) • Order 丨 -17- This paper size applies Chinese National Standard (CNS) A4 specifications ( 210X297 mm) 1236477 A7

以及 R、^與汉7各自為氫，R5與R8 —起形成 咪唑基係居於R-構形； R3、R4與R7各自為氫，尺5與&8一起形成 唑基係居於R-構形，或其氯化氫鹽； R3係為曱基，R4與R7各自為氫，R5與R8各 且咪唑基係居於R-構形；And R, ^, and Han 7 are each hydrogen, R5 and R8 together form an imidazolyl system and reside in the R-configuration; R3, R4, and R7 are each hydrogen, and rule 5 and & 8 together form an azolyl system in the R-configuration Form, or its hydrogen chloride salt; R3 is fluorenyl, R4 and R7 are each hydrogen, R5 and R8 are each and imidazolyl is in the R-configuration;

S 以及咪 自為正丁基 以及咪 R3、R4與R7各自為氫，“與“一起形成* 唑基係居於R_構形，或其氯化氫鹽； R與R各自為氫，R7為6-〇_CH广苯基，r5與尺8各自為正 丁基，且咪唑基係為構形與R-構形之消旋混合物； N-COOEt / 以 R、R4與R7各自為氫，^^與“一起形成、 及咪唑基係居於R-構形，或其氯化氫鹽； 一起形成 R3 、R4與R7各自為氫，r5與r /~\ \—广(CH2)2-苯基 以及咪唑基係居於R-構形； R3與R7各自為氫，R4為甲基，R5與R8各自為正丁基且咪 唑基係居於R-構形； R3與R4各自為氫，R7為7-氟基，R5與R8各自為正戊基， 且味唾基係為S-構形與R-構形之消旋混合物； -18 _ 本紙張尺度_巾目_鮮織# (210X297公釐) "~ ------- 1236477 A7 B7 五、發明説明（16 R、R4與R7各自為氫，⑴與…各自為正己基，且味唾基 係居於R-構形； 土 R、R與R7各自為氫，Rs為氫，而r8為居於s_構形之己 基，=及咪唑基係居於1構形，或其延胡索酸鹽； R、R4與R7各自為氫，R5與R8各自為正丁基，以及咪唑 基係居於R-構形，或其延胡索酸鹽；S and imid are n-butyl, and imids R3, R4, and R7 are each hydrogen, "together with" forms an azole group in the R_ configuration, or its hydrogen chloride salt; R and R are each hydrogen, and R7 is 6- 〇_CH phenyl, r5 and chi 8 are each n-butyl, and imidazolyl is a racemic mixture of configuration and R-configuration; N-COOEt / R, R4 and R7 are each hydrogen, ^^ Formed together with ", and the imidazolyl group is in the R-configuration, or its hydrogen chloride salt; together, it forms R3, R4, and R7 each is hydrogen, r5 and r / ~ \-广 (CH2) 2-phenyl, and imidazolyl R3 and R7 are hydrogen, R4 is methyl, R5 and R8 are n-butyl, and imidazolyl are in R-configuration; R3 and R4 are each hydrogen, and R7 is 7-fluoro , R5 and R8 are each n-pentyl, and the salivary system is a racemic mixture of S-configuration and R-configuration; -18 _ this paper size _ 巾 目 _ 鲜 织 # (210X297 mm) " ~ ------- 1236477 A7 B7 V. Description of the invention (16 R, R4 and R7 are each hydrogen, ⑴ and… are each n-hexyl, and the taste group is in the R-configuration; soil R, R and R7 is each hydrogen, Rs is hydrogen, and r8 is a hexyl group in the s_ configuration, = and imidazole A living system configuration, or fumarate; R, R4 and R7 are each hydrogen, R5 and R8 are each configured living R- is n-butyl and the imidazolyl-based, or fumarate;

R R與R各自為氫，R5與R8 —起形成 係居於R -構形； R、R4與R7各自為氫，R5與r8各自為正丁基，且咪唑基 係居於S-構形； 土 RlR4與R7各自為氫，R5與R8各自為乙基，且咪唑基係 居於R-構形； '、 R3、R4與R7各自為氫，“與尺8各自為正戊基，且咪唑基 係居於R-構形； R與&4各自為氫，R7為6-甲基，R5與R8各自為正丁基， 且咪唑基係為S-構形與R_構形之消旋混合物； R^R4各自為氫，R7為氟基，R5與R8各自為正丁基， 且咪唑基係為S-構形與R_構形之消旋混合物； R^R4各自為氫，R7為6·曱氧基，R5與R8各自為正丁 基且咪唑基係為S-構形與構形之消旋混合物； R與以4各自為氫，R7為基，R5與R8各自為正丁基， 且咪唑基係為S-構形與R-構形之消旋混合物； 以及咪唾基 -19-RR and R are each hydrogen, R5 and R8 together form the system R-configuration; R, R4 and R7 are each hydrogen, R5 and r8 are n-butyl, and the imidazolyl system is in the S-configuration; R1R4 And R7 are each hydrogen, R5 and R8 are each ethyl, and the imidazolyl group resides in the R-configuration; ', R3, R4, and R7 are each hydrogen, "each of which is n-pentyl with a ruler of 8 and the imidazolyl group is R-configuration; R and & 4 are each hydrogen, R7 is 6-methyl, R5 and R8 are each n-butyl, and the imidazolyl system is a racemic mixture of S-configuration and R_ configuration; R ^ R4 are each hydrogen, R7 is fluoro, R5 and R8 are each n-butyl, and the imidazolyl is a racemic mixture of S-configuration and R_ configuration; R ^ R4 is each hydrogen and R7 is 6 · Ethoxy, R5 and R8 are each n-butyl and imidazolyl is a racemic mixture of S-configuration and configuration; R and 4 are each hydrogen, R7 is based, R5 and R8 are n-butyl, And the imidazolyl system is a racemic mixture of S-configuration and R-configuration; and imidyl-19-

(請先閱讀背面之注意事項再填寫本頁) 、?τ— # 1236477(Please read the notes on the back before filling this page),? Τ— # 1236477

五、發明説明（17 R3與R4各自為氫，R7^5 t 8 ^ R為6-氟基，R5與R8各自為正丁美， 咪唑基係為S-構采IP 4盘 土 • 一 -構形之消旋混合物，或其氣化氫 R與11各自為氫’ r7為基，R5與R8各自為正丁 A， 且口米唾基係為S-構形與R_構形之消旋混合物； " R3與R4各自為氫，A 6.甲基，R5與R8各自為正戊基， °米嗤基係為S-構形與R_構形之消旋混合物；或 R^R4各自為氫H氣基，R5與Μ各自為正丁基， 咪唾基係為S_構形與㈣形之消㈣合物，或其氯化氮 鹽。 群又更佳之具有式（Π)之化合物係為那些選自下列 群中之化合物： R R與R各自為氫，R5為氫，而r8為居於8_構形之己 土以及米ϋ坐基係居於R-構形，或其延胡索酸鹽； R3、R4與R7各自為氫，R5與R8各自為正丁基，以及咪唑 基係居於R-構形，或其延胡索酸鹽； 且 鹽 且 且V. Description of the invention (17 R3 and R4 are each hydrogen, R7 ^ 5 t 8 ^ R is 6-fluoro group, R5 and R8 are each n-butyl, and the imidazolyl system is S-structured IP 4 plate soil • 1- A racemic mixture of configurations, or its vaporized hydrogens R and 11 are each hydrogen 'r7 as a base, R5 and R8 are each n-butyl A, and the saliva system is the S-configuration and R_ configuration. &Quot; R3 and R4 are each hydrogen, A 6. methyl, R5 and R8 are each n-pentyl, and the memidyl system is a racemic mixture of S-configuration and R-configuration; or R ^ R4 is each a hydrogen H gas group, R5 and M are each a n-butyl group, and the sialyl group is a S-configuration and a hydrazone-type elimination compound, or a nitrogen chloride salt thereof. A more preferred group has the formula (Π The compounds of) are those selected from the group consisting of: RR and R are each hydrogen, R5 is hydrogen, and r8 is self-dwelling soil in the 8-configuration and the melanyl group is in the R-configuration, or Fumarate; R3, R4, and R7 are each hydrogen, R5 and R8 are each n-butyl, and the imidazolyl is in the R-configuration, or its fumarate; and the salt is and

R3、R4與R7各自為氫，R5與R8 —起形成 唑基係居於R_構形； R3、R4與R7各自為氫，R5與R8各自為正丁基，且咪唑基 係居於S -構形； R3、R4與R7各自為氫，R5與R8各自為乙基，且咪唑基係 居於R_構形； 以及咪 •20- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)R3, R4, and R7 are each hydrogen, R5 and R8 together form an azole group and reside in the R_ configuration; R3, R4, and R7 are each hydrogen; R5 and R8 are each an n-butyl group; and the imidazolyl group is in the S-configuration R3, R4, and R7 are each hydrogen, R5 and R8 are each ethyl, and the imidazolyl group is in the R_ configuration; and mi • 20- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ) (Please read the notes on the back before filling this page)

1236477 A7 -----_ Β7 五、發明説明（18 ) R R與R各自為氫’ r^r8各自為正戊基，且味嗤基 係居於R-構形； R3、R4與R7各自A^ _ S马虱，R5為曱基，而R8為環己基，且咪 唾基係居於R-構形； R^R4各自為氫，R7為6-甲基，R5與R8各自為正丁基， 且^基係為S·構形與構形之消旋混合物；或 R#R各自為氫’ R7為氟基，R5與R8各自為正丁基， 且味，基係為S·構形與[構形之消旋混合物； R與R各自為氫，R7為卜甲氧基，r^r8各自為正丁 基’且咪嗤基係為s_構形與R_構形之消旋混合物； R^R4各自為氫，R7為6·Μ基，R5與R8各自為正丁基， 且味唾基係為S-構形與R_構形之消旋混合物； R>R4各自為氫’ R7為6_1基，R5與R8各自為正丁基， 且咪唑基係為S-構形與R_構形之消旋混合物，或其氣化氫 fftte · 盟， R與R4各自為氫，！^為8_甲基，R5與R8各自為正丁基， 且咪唑基係為S-構形與R_構形之消旋混合物； R與R4各自為氫，R7為6_甲基，R5與R8各自為正戊基， 且咪唑基係為S-構形與R_構形之消旋混合物；以及 R與R4各自為氫，r7為6_氣基，R5與R8各自為正丁基， 且咪唑基係為S-構形與R_構形之消旋混合物。 在另一方面，本發明係針對一種藥學組成物，其包含 有如上所界定的一或多種具有式（I)與式（II)之化合物或此 21 -1236477 A7 -----_ B7 V. Description of the invention (18) RR and R are each hydrogen 'r ^ r8 is n-pentyl, and the miso group is in the R-configuration; R3, R4, and R7 are each A ^ S horse lice, R5 is fluorenyl, and R8 is cyclohexyl, and the imidyl group is in the R-configuration; R ^ R4 is each hydrogen, R7 is 6-methyl, and R5 and R8 are each n-butyl And R ^ is a racemic mixture of S · configuration and configuration; or R # R is each hydrogen 'R7 is a fluoro group, R5 and R8 are each n-butyl group, and the taste is based on the S · configuration And a racemic mixture of the configuration; R and R are each hydrogen, R7 is bumethoxy, r ^ r8 is each n-butyl ', and the imidino system is the racemic configuration of s_ and R_ Mixture; R ^ R4 are each hydrogen, R7 is 6.M group, R5 and R8 are each n-butyl, and the sialyl group is a racemic mixture of S-configuration and R_ configuration; R > R4 are each Hydrogen 'R7 is a 6_1 group, R5 and R8 are each n-butyl, and the imidazolyl system is a racemic mixture of S-configuration and R_ configuration, or a gaseous hydrogen fftte · union thereof, and R and R4 are each hydrogen ,! ^ Is 8-methyl, R5 and R8 are each n-butyl, and imidazolyl is a racemic mixture of S-configuration and R_ configuration; R and R4 are each hydrogen, R7 is 6-methyl, and R5 And R8 are each n-pentyl, and the imidazolyl system is a racemic mixture of S-configuration and R_ configuration; and R and R4 are each hydrogen, r7 is 6-amino, and R5 and R8 are each n-butyl. And the imidazolyl system is a racemic mixture of the S-configuration and the R-configuration. In another aspect, the present invention is directed to a pharmaceutical composition comprising one or more compounds having formula (I) and formula (II) as defined above or this 21-

本紙張尺度相中國國家鮮（⑽）A4規格⑵GX29%D (請先閱讀背面之注意事項再填寫本頁) 裝—The size of this paper is similar to China's national fresh (⑽) A4 size⑵GX29% D (Please read the precautions on the back before filling this page)

、可I 1236477Can I 1236477

等之一藥學上可接受之趟_ 風類’以及具有式⑴與式（II)之化 合物載劑。 (請先閱讀背面之注意事項再填寫本頁) 在又另-方面，本發明係針對一種用以於一需要激發 來自於一或多種生長激素釋放抑制因子受體亞型之同效劑 作用的個體體内激發該作用之方法，其包括對該個體投藥 以一種如上所界定的具有式⑴與式（Π)之化合物或該化合 物之一藥學上可接受之鹽類。 在又另-方面，本發明係針對一種用以於一需要激發 來自於-或多種生長激素釋放抑制因子受體亞狀抬抗劑 作用的個體體内激發該作用之方法，其包括對該個體投藥 以-種如上所界定的具有式⑴與式（π)之化合物或該化合 物之一藥學上可接受之鹽類。 在又另一方面，本發明係針對一種於一需要結合一或 多種生長激素釋放抑制因子受體亞型的個體體内來產生該 結合之方法，其包括對該個體投藥以一種如上所界定的具 舞 有式（I)與式（II)之化合物或該化合物之一藥學上可接受之 鹽類。 在又另一方面，本發明係針對一種於一需要治療下列 疾病的個體來給予治療之方法：肢端肥大症、再狹窄、克 隆氏病（Crohn’s disease)、全身性硬化症、外部與内部胰臟 假囊腫與腹水、血管活性腸多肽瘤（VIPoma)、胰島母細胞 增殖、胰島素過多、促胃液素瘤（gastrin〇nia)、佐林哲-艾 力松症候群（Zollinger-Ellison Syndrome)、腹瀉、AIDS-相 關的腹瀉、化學治療相關的腹瀉、硬皮病、刺激性腸症候 -22- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 A7 _______B7_ 五、發明説明（20 ) (請先閲讀背面之注意事項再填寫本頁) 群、胰炎、小腸阻塞、胃食道回流、庫辛氏症候群（Cushing，s Syndrome)、促性腺瘤（gonadotropinom)、曱狀旁腺機能亢 進、突眼性甲狀腺腫（Graves，Disease)、糖尿病性神經病 變、佩吉特氏並（Paget’s disease)、多囊卵巢病（polycystic ovary disease)、癌症、癌惡病質、血壓過低、食後血壓過 低、恐慌發作、GH分泌性腺瘤以及TSH分泌性腺瘤，該方 法包括對該個體投藥以一種如上所界定的具有式⑴與式 (Π)之化合物或該化合物之一藥學上可接受之鹽類。 本發明之另一個方面係提供一種於一需要治療下列 疾病的個體來給予治療之方法：糖尿病，高血脂質症，胰 島素不敏性，X症候群，血管病，增殖性視網膜病，dawn phenomenon與腎病；胃酸分泌之抑制且特別是消化性潰 癌，腸與皮膚的以及胰與皮膚的瘻管，傾倒症候群，急性 或慢性胰炎與胃腸激素分泌腫瘤，企管發生之抑制，發炎 性疾病（諸如關節炎）之治療；慢性同種異體移植排斥，血 管成形術，防止移植物血管與胃腸出血，該方法包括對該 個體投藥以一種如上所界定的具有式⑴與式（π)之化合物 或該化合物之一藥學上可接受之鹽類。 在又另一方面，本發明提供一種於一需要抑制幽門螺 旋桿菌外/州·)之增殖的個體來給予該抑制之 方法，其包括對該個體投藥以一種如上所界定的具有式⑴ 與式（II)之化合物或該化合物之一藥學上可接受之趟類。 -23· 本紙張尺度適财關家標準（CNS) A4規格⑵QX297公楚)~~ ^ ------- 1236477One of them is a pharmaceutically acceptable trip_wind type 'and a compound carrier having formula (II) and formula (II). (Please read the precautions on the back before filling out this page) In another aspect, the present invention is directed to a synergist that is required to stimulate the action of one or more growth hormone release inhibitor receptor subtypes. A method for stimulating the effect in an individual, which comprises administering to the individual a compound having formula (I) and formula (II) or a pharmaceutically acceptable salt of the compound as defined above. In yet another aspect, the invention is directed to a method for stimulating an effect in a subject in need of stimulating an action from one or more growth hormone release inhibitory receptor subtype antagonists, which comprises The drug is administered as a compound having the formula (I) and formula (π) or a pharmaceutically acceptable salt of the compound as defined above. In yet another aspect, the invention is directed to a method for producing such binding in an individual in need of binding to one or more growth hormone release inhibitory factor subtypes, which comprises administering to the individual a drug as defined above Compounds of formula (I) and formula (II) or a pharmaceutically acceptable salt of the compound. In yet another aspect, the present invention is directed to a method of administering treatment to an individual in need of treatment of: acromegaly, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreas Visceral pseudocysts and ascites, vasoactive intestinal polypeptide tumor (VIPoma), islet blast proliferation, excessive insulin, gastroinoma, Zollinger-Ellison Syndrome, diarrhea, AIDS-related diarrhea, chemotherapy-related diarrhea, scleroderma, irritable bowel syndrome-22- This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) 1236477 A7 _______B7_ V. Description of the invention (20) (Please read the precautions on the back before filling out this page) group, pancreatitis, small intestinal obstruction, gastroesophageal reflux, Cushing's Syndrome, gonadotropinom, hyperparathyroidism, Graves (Disease), diabetic neuropathy, Paget's disease, polycystic ovary disease ), Cancer, cancer cachexia, hypotension, hypotension after eating, panic attack, GH-secreting adenoma, and TSH-secreting adenoma, the method comprises administering to the individual a formulae having the formula ⑴ and formula (Π) as defined above. Or a pharmaceutically acceptable salt of the compound. Another aspect of the present invention provides a method for administering treatment to an individual in need of treatment of the following diseases: diabetes, hyperlipidemia, insulin insensitivity, syndrome X, vascular disease, proliferative retinopathy, dawn phenomenon and kidney disease Inhibition of gastric acid secretion and in particular digestive ulcers, fistulas of the intestine and skin and pancreas and skin, dumping syndrome, acute or chronic pancreatitis and gastrointestinal hormone secretion tumors, inhibition of business development, inflammatory diseases such as arthritis ) Treatment; chronic allograft rejection, angioplasty, to prevent graft vascular and gastrointestinal bleeding, the method comprises administering to the individual a compound of formulae ⑴ and (π) or one of the compounds as defined above Pharmaceutically acceptable salts. In yet another aspect, the present invention provides a method for administering inhibition to an individual in need of inhibiting the proliferation of H. pylori, which comprises administering to the individual a formula having the formula ⑴ and formula as defined above. A compound of (II) or a pharmaceutically acceptable route. -23 · This paper is suitable for financial standards (CNS) A4 size (QX297). ~~ ^ ------- 1236477

Ι1ΙΙΙΙΙ1 — — — — — — — — — — — — 丨 — III (請先閲讀背面之注意事項再填寫本頁) 在又另-方面，本發明提供一種於一需要阻斷納通道 的個體來給予該阻斷之方法，其包括對該個體投藥以一種 具有式（I)之化合物或該化合物之一藥學上可接受之鹽類。 在又另-方面，本發明提供一種於一需要阻斷:通道 的個體來給予該阻斷之方法，其包括對該個體投藥以一種 具有式（II)之化合物或該化合物之一藥學上可接受之鹽類。 在又另一方面，本發明提供一種於一需要緩解神：病 變性疼痛的個體來給予該緩解之方法，其包括對該個體投 藥以一種具有式（I)之化合物或該化合物之一藥學上可接 受之鹽類。 -、=& ' 在又另-方面，本發明提供一種於一需要緩解神經病 變性疼痛的個體來給予該緩解之方法，其包括對該個體投 藥以一種具有式（II)之化合物或該化合物之一藥學上可接 受之鹽類。 在又另-方面，本發明提供一種供用作為一局部麻醉 劑之藥學組成物，其包括一種具有式⑴之化合物或該化合 物之一藥學上可接受之鹽類，以及一任擇的藥學上可接2 之稀釋劑。 x 在又另-方面，本發明提供一種供用作為一局部麻醉 劑之藥學組成物，其包括—種具有式（π)之化合物或該化合 物之一藥學上可接受之鹽類，以及一任擇的藥學上可接受 之稀釋劑。 在又另一方面，本發明提供一種於一需要治療任一種 在病因學上涉及到麵胺酸鹽釋出之病理學、疾病或臨床病 -24- --------—----- 本紙張尺度適用中國國家標準（CNS) Α4規格（2】0Χ297公釐） 1236477 A7 B7 五、發明説明 22 狀的個體來給予該治療之方法，纟包括對該個體投藥以一 種具有式（I)之化合物或該化合物之—藥學上可接受之鹽 類。此前述方法之-個較佳方法是其中該病理學疾病或 臨床病狀係選自於下列群中：精神、忘與严― 贯砰病學疾病、激素病狀、 代謝引起的腦損害、亞硫酸鹽氧化梅不足、與肝衰竭有關 的肝性腦病、°區吐，痙攣，癲癇、耳鳴，疼痛以及藥物濫 用與戒斷。 在又另-方面’本發明提供一種於一需要治療任一種 出之病理學、疾病或臨床病 狀的個體來給予該治療之方法，其包括對該個體投藥以一 種具有式（II)之化合物或該化合物之一藥學上可接受之 類。此前述方法之一個較佳方法是其中該病理學、：病 臨床病狀係選自於下列群中：精神病學疾病、激素病狀 代謝引起的腦損害、亞硫酸鹽氧化酶不足、與肝衰竭有 的肝性腦病、嘔吐，痙f，癩癇、耳鳴，疼痛以及藥物濫 用與戒斷。 在又另一方面，本發明提供一種於一需要治療任 涉及神經元損害之病理學的個體來給予該治療之方法穴 包括對該個體投藥以一種具有式⑴之化合物或該化合物 之一藥學上可接受之鹽類。此前述方法之一個較佳方法是 其中該病理學係選自於下列群中：阿滋海默氏症，杭丁 氏症或帕金森氏症，病毒（包含HIV)誘發的神經退化，肌 縮性脊髓側索硬化症（ALS)，核上的癱瘓，下撖欖體橋 小腦萎縮（OPCA),以及環境與外源性神經毒素之作用。 rf^g 鹽 或 關 種 其 頓 萎 腦 •25- 本紙張尺度適用中國國家標準（CNS) A4規格（2]〇χ297公釐 (請先閲讀背面之注意事項再填寫本頁)Ι1ΙΙΙΙΙΙ1 — — — — — — — — — — — 丨 — III (Please read the notes on the back before filling out this page) In another aspect, the present invention provides an individual who needs to block the nanochannel to give The method of blocking comprises administering to the individual a compound having formula (I) or a pharmaceutically acceptable salt of the compound. In yet another aspect, the present invention provides a method for administering the block to an individual in need of a block: channel, which comprises administering to the individual a compound having formula (II) or a pharmaceutically acceptable compound. Accepted salts. In yet another aspect, the present invention provides a method of administering to a subject in need of relief from pathological pain: comprising administering to the subject a compound having formula (I) or one of the compounds pharmaceutically Acceptable salts. -, = &Amp; 'In yet another aspect, the present invention provides a method for administering a neuropathic pain to an individual in need thereof, which comprises administering to the individual a compound having the formula (II) or the compound One of the pharmaceutically acceptable salts. In yet another aspect, the present invention provides a pharmaceutical composition for use as a local anesthetic, which comprises a compound having the formula ⑴ or a pharmaceutically acceptable salt of the compound, and an optional pharmaceutically acceptable 2 The thinner. x In yet another aspect, the present invention provides a pharmaceutical composition for use as a local anesthetic, comprising a compound of formula (π) or a pharmaceutically acceptable salt of the compound, and an optional medicament Acceptable diluent. In yet another aspect, the present invention provides a pathological, disease, or clinical condition that requires treatment of any of the glutamate releases in need of treatment-24 ------------- --- This paper size applies the Chinese National Standard (CNS) A4 specification (2) 0 × 297 mm 1236477 A7 B7 V. Description of the invention 22 The method of administering this treatment to an individual with a shape of 22 includes administering to the individual a formula The compound of (I) or a pharmaceutically acceptable salt of the compound. A preferred method of the foregoing method is one in which the pathological or clinical condition is selected from the group consisting of: mental, forgetfulness and strictness-bang disease, hormonal conditions, metabolic brain damage, Sulfate oxidized plum deficiency, hepatic encephalopathy associated with liver failure, ° vomiting, spasms, epilepsy, tinnitus, pain, and drug abuse and withdrawal. In yet another aspect, the invention provides a method of administering to a subject in need of treatment any one of the pathological, disease or clinical conditions, which comprises administering to the subject a compound of formula (II) Or one of the compounds is pharmaceutically acceptable or the like. A preferred method of the foregoing method is wherein the pathology, the clinical pathology of the disease is selected from the group consisting of: psychiatric disease, brain damage caused by hormonal disease metabolism, insufficient sulfite oxidase, and liver failure Some have hepatic encephalopathy, vomiting, spasms, epilepsy, tinnitus, pain, and drug abuse and withdrawal. In yet another aspect, the present invention provides a method of administering to an individual in need of treatment any pathology involving neuronal damage, comprising administering to the individual a compound having the formula (I) or one of the compounds. Acceptable salts. A preferred method of the aforementioned method is that the pathology is selected from the group consisting of Alzheimer's disease, Hunting's disease or Parkinson's disease, viral (including HIV) -induced neurodegeneration, muscle contraction Lateral spinal cord sclerosis (ALS), nuclear paralysis, inferior corpus callosum cerebellar atrophy (OPCA), and environmental and exogenous neurotoxin effects. rf ^ g salt or swollen withered brain • 25- This paper size applies Chinese National Standard (CNS) A4 specification (2) 〇297mm (Please read the precautions on the back before filling this page)

1236477 A7 一 "" —-— B7__________ 五、發明説明（23 ) 在又另一方面，本發明提供一種於一需要治療任一種 涉及神經元損害之病理學的個體來給予該治療之方法，其 包括對該個體投藥以一種具有式（„)之化合物或該化合物 之一藥學上可接受之鹽類。此前述方法之一個較佳方法是 其中該病理學係選自於下列群中：阿滋海默氏症，杭丁頓 氏症或帕金森氏症，病毒（包含HIV)誘發的神經退化，肌萎 縮性脊髓側索硬化症（ALS)，核上的癱瘓，下橄欖體橋腦 小腦萎縮（OPCA)，以及環境與外源性神經毒素之作用。 在又另一方面，本發明提供一種於一需要治療心律不 齊的個體來給予該治療之方法，其包括對該個體投藥以一 種具有式（I)之化合物或該化合物之一藥學上可接受之鹽 在又另一方面，本發明提供一種於一需要治療心律不 齊的個體來給予該治療之方法，其包括對該個體投藥以一 種具有式（II)之化合物或該化合物之一藥學上可接受之鹽 類。 在又另一方面，本發明提供一種於一需要治療癲癇的 個體來給予該治療之方法，其包括對該個體投藥以一種如 本案申請專利範圍第1項之化合物或該化合物之一藥學上 可接受之鹽類。 在又另一方面，本發明提供一種於一需要治療癲癇的 個體來給予該治療之方法，其包括對該個體投藥以一種如 本案申请專利範圍第12項之化合物或該化合物之一藥學上 可接受之鹽類。 -26- 本紙張尺度適用中國國家標準（CNS) Α4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) ·-"· 1236477 A7 Γ^-~~ --!Ζ_ _ 五、發明説明（24 ) ^ ^ 一—— 發明之詳細說明 熟習此項技術人士將會認知到，本發明中所提列之若 干取代基，當與本案化合物中之另一者或雜原子組合時， 可具有降低的化學安定性。該等具有降低的化學安定性之 I 化合物係較不佳的。 一般而言，具有式（I)與式（11)之化合物可藉由包含化 學技藝中用於生成化合物之方法之製程而被製造出。一些 用於製造具有式（I)與式（II)之化合物的方法被提供以作為 本發明之進一步特徵並藉由隨後之反應示意圖與實施例來 I 例證之。 所有於本發明揭露内容中提到之參考文獻與專利在 此併入本案以為參考資料。 | 在别述之結構化學式以及本發明全文中，除非另有提 | 及’下列之術5吾具有本文所示之意義： 烷基基團係意欲包含那些呈直鏈或分支構形之具有 指定長度的烷基基團。該等烷基基團之實例有甲基、乙基、 丙基、異丙基、丁基、二級丁基、三級丁基、戊基、異戊 基、己基、異己基等等。 當C〇-烷基之定義出現時，其表示一個單一的共價鍵。 如前述所特定之烷氧基基團係意欲包含那些呈直鏈 或分支構形之具有指定長度的烷氧基基團。該等烷氧基基 團之實例有甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、 異丁氧基、三級丁氧基、戊氧基、異戊氧基、己氧基、異 己氧基等等。 -27- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公楚） (請先閲讀背面之注意事項再填寫本頁)1236477 A7-"B7__________ V. Description of the Invention (23) In yet another aspect, the present invention provides a method for administering the treatment to an individual in need of treating any pathology involving neuronal damage, It includes administering to the individual a compound of formula („) or a pharmaceutically acceptable salt of the compound. A preferred method of the aforementioned method is where the pathology department is selected from the group: Zimmerheimer's disease, Huntington's disease or Parkinson's disease, virus (including HIV) -induced neurodegeneration, amyotrophic lateral sclerosis (ALS), paralysis of the nucleus, hypopontine cerebellum Atrophy (OPCA), and the effects of environmental and exogenous neurotoxins. In yet another aspect, the present invention provides a method of administering to a subject in need of treatment for arrhythmia, which comprises administering A compound having formula (I) or a pharmaceutically acceptable salt of the compound. In yet another aspect, the present invention provides a method for administering to a subject in need of treatment for arrhythmia. A method comprising administering to the individual a compound having formula (II) or a pharmaceutically acceptable salt of the compound. In yet another aspect, the invention provides an individual in need of treatment for epilepsy to administer the A method of treatment, which comprises administering to the individual a compound or a pharmaceutically acceptable salt of the compound as described in item 1 of the patent application scope. In yet another aspect, the present invention provides a method for treating epilepsy in need thereof. A method for administering the treatment to an individual includes administering to the individual a compound such as the patent scope of the present application for item 12 or a pharmaceutically acceptable salt of the compound. -26- This paper applies Chinese national standards (CNS) Α4 specifications (210X297 mm) (Please read the precautions on the back before filling this page) ·-" · 1236477 A7 Γ ^-~~-! Z_ _ V. Description of the invention (24) ^ ^ 1 —— Detailed description of the invention Those skilled in the art will recognize that certain substituents mentioned in the present invention, when combined with another or heteroatom in the compound of the present case, may have reduced The chemical stability of these I compounds with reduced chemical stability is less favorable. In general, compounds with formula (I) and formula (11) can be used to generate compounds by using chemical techniques The process of the method is manufactured. Some methods for manufacturing compounds having formula (I) and formula (II) are provided as further features of the present invention and are exemplified by the following reaction schemes and examples. All references and patents mentioned in the disclosure of the present invention are hereby incorporated into this case for reference. | In the structural chemical formulas mentioned elsewhere and in the full text of the present invention, unless otherwise mentioned | Significance shown: Alkyl groups are intended to include those alkyl groups having a specified length in a linear or branched configuration. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl and the like. When the definition of Co-alkyl appears, it represents a single covalent bond. The alkoxy group as specified above is intended to include those having a specified length in a linear or branched configuration. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, isopentyloxy , Hexyloxy, isohexyloxy, etc. -27- This paper size applies to China National Standard (CNS) A4 (210X297). (Please read the precautions on the back before filling this page)

1236477 五、發明説明（25 ) 破。由素或函基此術語係意欲包含齒素原子氟、氣、漠與 環燒基此術語係意欲包含具有熟習此藝者 不石反數的單-環燒基（例如，環戊基、環己基等等）、雙斤 ^如’雙環Μ·1]庚·2,5_二物)或三環烧基(例：： 剛说基等等）’内部任擇地具有雙鍵或三鍵。 芳基此術語係意欲包含本技藝所知之芳族環， 為單環、雙環或三環，諸如苯基、萘基、茚基、奠基與葱。 雜環此術語包含具有-或多個雜原子(諸如氧、氮和/ 或硫）之單環、雙環或三環系統。該等環系統可為芳族的， 例如吨咬、㈣、料、射、嚷吩（亦知之為嚷吩基）、 呋喃、苯並嘍吩、四唑、二氫吲哚、吲唑、Ν_甲醯基吲哚' 苯並味嗤、咳唾與变二嗅。該等環系統可為非芳族的例 如11比略σ定、旅唆、嗎琳等等。 出現於本案申請專利範圍中之下面敘述所意指的·· “R9與R1G與其等所連接之氮一起形成一個包含有Μ 與R1G所連接之該氮原子的具有5至8個成員之環，其中該環 的成員中之一者可任擇地為一個氧原子或Nr11，其中r11 為（q-Q)烷基、-chohcvd 烷基、-c(〇)_nh2、 -C(0)-NH-(Cl-C6)烷基、_C(0)-NH-[(Cl-C6)烷基]2、 C(S)-NH2、-C⑻-NH-(Cl-C6)烧基、-C⑻·nh_[(Ci_C6)烷基]2 或經任擇取代的-苯基-(Co-C6)烧基”係為下列部分之形式 造成： -28- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)1236477 Fifth, the description of the invention (25) broken. This term is intended to include halo atoms such as fluorine, gas, molybdenum, and cycloalkenyl. The term is intended to include mono-cycloalkenyl groups (e.g., cyclopentyl, cyclo Hexyl, etc.), double catty ^ such as 'bicyclic M · 1] heptane · 2,5_ two things) or tricyclic alkyl (for example: just said base, etc.)' internally has a double or triple bond . The term aryl is intended to include aromatic rings known in the art, which are monocyclic, bicyclic, or tricyclic, such as phenyl, naphthyl, indenyl, benzyl, and onion. Heterocyclic This term encompasses monocyclic, bicyclic, or tricyclic systems having-or more heteroatoms such as oxygen, nitrogen, and / or sulfur. These ring systems can be aromatic, such as ton, fluorene, sulfonium, pyrene, fluorene (also known as fluorenyl), furan, benzofluorene, tetrazole, indole, indazole, N _Methylsulfonyl indole 'Benzo miso, cough and salivation. These ring systems can be non-aromatic, such as 11 sigma sigma, Luan, Morin and so on. Appearing in the scope of the patent application of the present application is meant as follows: "R9 and R1G together with the nitrogen to which they are attached form a ring of 5 to 8 members containing the nitrogen atom to which M and R1G are connected, One of the members of the ring is optionally an oxygen atom or Nr11, where r11 is (qQ) alkyl, -chohcvd alkyl, -c (〇) _nh2, -C (0) -NH- ( Cl-C6) alkyl, _C (0) -NH-[(Cl-C6) alkyl] 2, C (S) -NH2, -C⑻-NH- (Cl-C6) alkyl, -C⑻nh_ [ "(Ci_C6) alkyl] 2 or optionally substituted -phenyl- (Co-C6) alkyl" is caused by the form of the following parts: -28- This paper size applies to China National Standard (CNS) A4 specifications (210X297 Mm) (Please read the notes on the back before filling in this page)

12364771236477

發明說明（26Invention Description (26

NR11 -NR9R10 弧表示該環之碳成員(，是，，其中Rl1係如前所定義，而 等需要等數目之碳)㈣弧之對稱並不意欲表示其 歧人Γ—般技藝之化學家會認知到，本發明中所列出的某 3雜原子之取代基的組合所界定之化合物生理條件下 為不安定者。因此，該等化合物係為較不佳的。 當-個如此處所用之化學結構具有一個由之發出的 前说…箭號表示連接之點。例如，結構 係為一個戊基基團。當一個箭號係 由一個環部分被拉出時， ^ 4前唬表不該環可被連接至可用 (請先閲讀背面之注意事項再填寫本頁)The NR11 -NR9R10 arc represents the carbon member of the ring (, yes, where Rl1 is as defined before, and so on, which requires an equal number of carbons). The symmetry of the arc is not intended to indicate its disparity. It is recognized that compounds defined by the combination of certain 3 heteroatom substituents listed in the present invention are unstable under physiological conditions. Therefore, these compounds are less favorable. When a chemical structure, as used herein, has a preface ... the arrow indicates the point of connection. For example, the structure is a pentyl group. When an arrow is pulled out by a ring, ^ 4 indicates that the ring can be connected to available (please read the precautions on the back before filling this page)

訂| 的鍵結點之任一者處，例如Order | at any of the key nodes, such as

意指苯基可相對於X 基：被鍵結至鄰位、間位或對位處。當一個箭號係由一個 雙衣或部分被拉出時，該箭號表示該雙環或三環可被 連接至該等環之任-者内之可用的鍵結點之任一者處，例It means that the phenyl group may be relative to the X group: bonded to the ortho, meta or para position. When an arrow is drawn from a double coat or part, the arrow indicates that the double or triple ring can be connected to any of the available bond points within any of those rings, for example

壤部分被鍵結 意指°引嘴係藉由該環之苯基部分或含氮 -29- 本紙張尺度適用中國國家標準（CNS) Α4規格（210X297公爱） 1236477 A7 B7 五 發明説明 27 之 在有關於式（II)之界定中，當R5與R8與其等所連接 ★ 兔原子被界定為，例如 (請先閱讀背面之注意事項再填寫本頁) 時，環中之*係 表示其為R與R8所連接之碳原子，因而形成一個螺狀化合 物。 具有下列核結構之本發明化合物依據下列方案被編 號：The soil part is bonded means that the lead is through the phenyl part of the ring or nitrogen-containing. 29- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 public love) 1236477 A7 B7 Five invention description 27 of In the definition of formula (II), when R5 and R8 are connected to them ★ Rabbit atom is defined as, for example (please read the notes on the back before filling this page), the * in the ring means it is The carbon atom to which R and R8 are attached forms a spiro compound. The compounds of the invention having the following nuclear structures are numbered according to the following scheme:

.、可| 治療意表一哺乳動物體（特別是人類）内之一病 的任何治療，且包括： (1)對一可能易於罹患一疾病但尚未被診斷出帶有 疾病之個體防止其發生該疾病； (Η)抑制該病狀，亦即遏止該病狀之發展； (ii〇舒緩該病狀，亦即舒緩疼痛之癥候。 個體此術語意表本發明化合物之接受者，較佳 一哺乳動物，且更佳為人類。 可藉由一納通道阻斷劑之投藥來治療的疾病 心、係思奴/函蓋一般為本技藝認知為通常可利用鈉通道 斷劑而予以有用地治療之所有疾病狀態，以及那些已被 現可利用本發明之鈉㉟道阻斷劑（即具有式⑴與式⑴）之 _ 30- 本紙張尺度適用中國國家標準（CNS) 1236477 A7 B7 發明說明（ 合物）而予以有用地、Λ底 ^ 口療之疾病狀態。該等疾病狀態包含， ]一不限於，周圍神姆、忘 、、病虼，諸如三叉神經痛、治療後神經 '甬、糖尿病性神經病變、 (請先閲讀背面之注意事項再填寫本頁) 舌因神經痛、腰與頸神經根痛、 反射交感性營養不良以Β⑷_ 及灼痛，以及轉移性浸潤、痛性肥 胖病與燒傷後發生的神經 夕 T、士病變，以及在中風、視丘損害與 夕發性硬化症後之中樞疼痛病狀。 或錢合物之藥學上可接受之鹽類被投藥至-需要該治療 =哺乳動物時，能充分達成如前所界定之治療的那個數 量/口療有效數量會視要被治療之個體以及疾病狀態、痛 古之厭重度、投藥之方式而定，且可為熟習此項技術人士 來例仃地決疋之。“治療有效數量,、匕術語被隱含地併入 於在本發明之_方法中被投藥的化合物之數量中，或當該 化合物係為本發明之醫藥學組成物之一組份時。 如則述結構式⑴與式（II)中之星號所標示的，本發明 之化合物具有至少一個不對稱中心。額外的不對稱中心視 A刀子上之可各種不同的取代基而定而會存在於該分子 上。各該不對稱中心會產生兩個光學異構物，而於此意欲 將所有該等光學異構物，就如分開的、純質的或部分純化 的光學異構物’此等之消旋或非對映體異構物混合物，都 包含在本發明之範疇内。 本發明化合物通常可被分離成為呈其藥學上可接受 的酸加成鹽之形式，諸如衍生自無機或有機酸之鹽類。該 等酸之實例有鹽酸、硝酸、硫酸、磷酸、乙酸、丙酸、馬 -31 - 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477Can treat any treatment intended for a disease in a mammalian body (especially a human) and includes: (1) Preventing an individual who may be susceptible to a disease but has not been diagnosed with the disease Disease; (ii) inhibit the condition, that is, stop the development of the condition; (ii) alleviate the condition, that is, relieve the symptoms of pain. The term individual means the recipient of the compound of the present invention, preferably a mammal Diseases that can be treated by the administration of a nanochannel blocker are generally considered to be useful in the treatment of sodium channel blockers, which are generally recognized by the art. Disease status, and those that have been used in the present invention sodium blockade blocking agent (that is, with formula ⑴ and formula ⑴) _ 30- This paper size applies the Chinese National Standard (CNS) 1236477 A7 B7 Invention Description (Compound ) And to be useful, Λ bottom ^ oral disease state. These disease states include,] not limited to, surrounding God, forget, disease, such as trigeminal neuralgia, post-treatment nerve '神经, diabetic nerve Lesion (Please read the precautions on the back before filling out this page) Tongue due to neuralgia, lumbar and cervical nerve root pain, reflex sympathetic dystrophy, β⑷_ and burning pain, as well as metastatic infiltration, painful obesity and burns Neuropathy T, sclerosis, and central pain symptoms after stroke, optic hill damage, and post-sclerosis. Or pharmacologically acceptable salts of money compounds are administered to-when the treatment is needed = mammal The quantity that can fully achieve the treatment as defined above / the effective quantity of oral treatment will depend on the individual to be treated and the disease state, the degree of pain and the way of administration, and it can be used by those skilled in the art For example, "therapeutic effective amount," the term is implicitly incorporated into the number of compounds administered in the method of the present invention, or when the compound is a pharmaceutical composition of the present invention As shown in the structural formula ⑴ and the asterisk in formula (II), the compound of the present invention has at least one asymmetric center. The additional asymmetric center can be obtained in various ways depending on the A knife. Depending on the substituent, it will exist on the molecule. Each asymmetric center will produce two optical isomers, and it is intended here that all such optical isomers are separated, pure or partially purified. The optical isomers of such racemic or diastereomeric mixtures are included within the scope of the present invention. The compounds of the present invention can generally be isolated into their pharmaceutically acceptable acid addition salts. Forms, such as salts derived from inorganic or organic acids. Examples of such acids are hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, and ma-31-This paper is sized to the Chinese National Standard (CNS) A4 (210X297) Mm) 1236477

發明説明 (請先閲讀背面之注意事項再填寫本頁) 來酸、琥王白酸、D-酒石酸、L-酒石酸、丙二酸、曱續酸等 等。此外，某些含有一個酸官能（諸如一個叛基）之化合物 可被刀離成為呈其無機鹽之形式，其中平衡離子可選自於 鈉、鉀、鋰、鈣、鎂等以及有機鹼。 藥學上可接受的鹽可藉由取！當量之具有式⑴與式（π) 之化合物並令之與大約i當量之所欲的鹽類之合適對應酸 接觸而被形成。所形成的鹽類之發展與分離係為熟習此項 技術人士所詳知的。 •、訂· 如本技藝所知的，生長激素釋放抑制因子之同效劑與 拮抗劑可用於治療許多不同種類之醫療病狀與疾病，諸如 幽門螺旋桿菌增殖之抑制、肢端肥大症、再狹窄、克隆氏 病、全身性硬化症、外部與内部胰臟假囊腫與腹水、血管 活性腸多肽瘤（VIPoma)、胰島母細胞增殖、胰島素過多、 促胃液素瘤（gastrinoma)、佐林哲艾力松症候群 (Zolhnger-Ellison Syndrome)、腹瀉、AIDS-相關的腹瀉、 化學治療相關的腹瀉、硬皮病、刺激性腸症候群、胰炎、 小腸阻塞、胃食道回流、十二指腸胃回流；以及用於治療 内分泌疾病和/或病狀，諸如庫辛氏症候群（Cushing，sDescription of the invention (please read the precautions on the back before filling this page) acid, humic acid, D-tartaric acid, L-tartaric acid, malonic acid, acetic acid, etc. In addition, some compounds that contain an acid function (such as a tether group) can be cleaved into the form of their inorganic salts, where the counterion can be selected from sodium, potassium, lithium, calcium, magnesium, and organic bases. Pharmaceutically acceptable salts can be taken by! An equivalent of the compound having formula (I) and formula (π) is formed by contacting it with a suitable corresponding acid of about i equivalent of the desired salt. The development and separation of the formed salts is well known to those skilled in the art. •, as defined in the art, synergists and antagonists of growth hormone release inhibitors can be used to treat many different types of medical conditions and diseases, such as inhibition of H. pylori proliferation, acromegaly, and Narrowing, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, vasoactive intestinal polypeptide tumor (VIPoma), islet blast proliferation, excessive insulin, gastrinomas (gastrinoma), Zolin Zheai Zolhnger-Ellison Syndrome, diarrhea, AIDS-related diarrhea, chemotherapy-related diarrhea, scleroderma, irritable bowel syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenal gastrointestinal reflux; and for Treatment of endocrine diseases and / or conditions such as Cushing's syndrome (Cushing, s

Syndrome)、促性腺瘤（g〇nad〇tropinom)、曱狀旁腺機能亢 進、突眼性曱狀腺腫（Graves’ Disease)、糖尿病性神經病 變、佩吉特氏並（Paget’s disease)以及多囊卵巢病 (polycystic ovary disease);用於治療各種類型之癌症，諸 如曱狀腺癌、肝細胞瘤、白血病、腦膜瘤以及與癌症相關 之病狀，諸如癌惡病質；用於治療諸如血壓過低之病狀， -32- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 五、發明説明（30 ) 諸如U性低血Μ與食後血μ過低與恐慌發作；gh分泌性 腺瘤以及TSH分泌性腺瘤。第2型但非第5型亞型受體之活 化係與治療催乳;數素分泌性腺瘤有關耳葬。其&與生長激素 釋放抑制因子亞型之活化有關聯的病徵有：姨島素和/或升 血糖激素之抑制且特別是糖尿病，高血脂質症，胰島素不 敏性，X症候群，血管病，增殖性視網膜病，d_ Phenomenon與腎病；胃酸分泌之抑制且特別是消化性潰 瘍，腸與皮膚的以及胰與皮膚的瘻管，傾倒症候群 (Dumping syndrome)，水瀉症候群，急性或慢性胰炎以及 胃腸激素分泌性腫瘤；血管發生之抑制，發炎性疾病（諸如 關節炎）之治療；慢性同種異體移植排斥；血管成形術；防 止移植物血管與胃腸出血。生長激素釋放抑制因子同效劑 亦可被使用於降低一病人之體重。因此，本發明之化合物 可供用於前述之方法中。 因此，本發明在其範疇内包含藥學組成物，該組成物 包含有作為一有效成分之至少一種具有式⑴與式（Π)之化 合物並締合以一藥學上可接受之載劑。 本發明之化合物可藉由口服的、非經腸道的（例如肌内 的、腹腔内的、靜脈内的或皮下的注射，或植入物）、鼻内 的、陰道的、直腸的、舌下的投藥或局部投藥的途徑，且 可與藥學上可接受之載劑被配方以提供適合供各種投藥途 徑之用的劑量形式。 供口服投藥用之固體劑量形式包含膠囊、錠劑、藥 丸、粉末與顆粒。在該等固體劑量形式中，有活性的化合 -33- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 A7 五、發明説明（31 j 物被混合以至少一種情性的藥學上可接受之載劑，諸如薦 糖乳糖或瓜粉。該等劑量形式亦可包含有除了該等惰性 稀釋知]之外在通*實施上會有之額外物質，例如潤滑劑（諸 如硬脂酸納）。就膠囊、錠劑與藥丸之例而言，該㈣㈣ 式亦可包含緩衝劑。旋劑與藥丸可額外地利用腸溶衣予以 製備之。 供口服投藥用之液體劑量形式包含藥學上可接受之 乳液、溶液、懸浮液、糖聚、含有本技藝慣常使用之惰性 稀釋劑的驰劑。此外，除了該等惰性稀釋劑，本案組成物 亦可含有佐劑（諸如濕潤劑、乳化劑與散浮劑），以及香化 劑、調味劑與加香劑。 供非經腸道的投藥用之依據本發明之製品包含無菌 水性或非水性溶液、懸浮液或乳液。非水性溶劑或載劑有 丙一醇、聚乙二醇、植物油(諸如撖欖油與玉米油)、明膠， 以及可注射之有機酯（諸如油酸乙酯）。該等劑量形式亦可 含有佐劑，諸如防腐劑、濕潤劑、乳化劑與分散劑。此等 "、菌處ί里爿如’藉由通經一個細菌滯留過遽器來過 ，，將併入無菌處理劑至組成物内，幸昌射照射組成物，或 是加熱組成物。此等亦可被致造成呈無菌固態組成物之形 式，該固態組成物在使用前能被溶於無菌水或某些其他無 菌可注射的基質中。 供直腸或陰道投藥用之組成物較佳地係為检劑，該检 劑除了活性物質之外可含有賦形劑，諸如可可奶油或检劑 壤0 -34- ………·…丨 (請先閲讀背面之注意事項再填寫本頁) 訂…------------- 本紙張尺度適用 (CNS) A4^ (210X297^7 1236477 A7 -----------B7__ 五、發明説明（32 ) ''' t、π内或舌下的投藥用之組成物亦可利用本技藝所 詳知之標準賦形劑來製備。 再者 個具有式（1)與式（II)之本發明化合物可呈一 持續釋放組成物之形式被投藥，諸如那些描述於下列專利 中者。美國專利第5,672,659號教示包含有一生物活性劑與 -聚酯之持續釋放組成物。美國專利第5,595，號教示包 含有呈一可膠凝形式的生物活性劑之持續釋放組成物。於 1997年9月9日提申的美國專利申請案第〇8/929,363號教示 包含有一生物活性劑與聚葡萄胺糖（chh〇san)之聚合性持 續釋放組成物。於^如年丨丨月！日提申的美國專利申請案第 08/740,778號教示包含有一生物活性劑與環糊精之持續釋 放組成物。於1998年1月29曰提申的美國專利申請案第 〇痛5,394號教示包含有_生物活性劑之可吸收的持續釋 放組成物。前述專利與申請案之教示在此併入本案以為參 考資料。 ' 一般而言，本案組成物中之一具有式⑴與式（π)之本 發明化合物的有效劑量可被變化之；但有必要的是，活性 組份的數量要能致使可獲得一適合的劑量形式。所選定之 劑量端視所欲之治療效用、投藥之途徑以及治療之期間而 疋’此荨因素皆屬於熟習此項技術人士之知識範缚内。一 般而言’介於每天0.0001至1〇〇 mg/kg體重之間的劑量位準 被投藥至人類及其他動物（例如哺乳動物）。 一個較佳的劑量範圍係為每天0.01至10 0⑺^“體 重，此可g成一個單一劑1或予以區分成數個劑量來投藥。 -35- 本紙張尺度賴中關家鮮（⑽）A4規格(210X297公& ' "~" -------------------ί 裝- (梦先閲讀背面之注意事項再填寫本頁) 訂— 1236477 A7 _____B7 _ 五、發明説明（33 ) 本發明之化合物可根據下列分析來評估其結合至生 長激素釋放抑制因子亞型受體之能力。 人類生長激素釋放抑制因子亞型受體結合研究： 一個化合物對於人類生長激素釋放抑制因子亞型受 體1至5 (分別為ssti、sst2、sst3、sst4與sst5)之親和力，係 藉由測定[125I-Tyrn]SRIF-14結合至CH0-K1轉染的細胞之 抑制作用來評估之。 將人類SSt!受體基因選殖成為一個基因組片段。一個 含有100 bp之5’-未轉譯區域、1·17 Kb之整個編碼區域以及 230 bp之3’-未轉譯區的1.5 Kb PwI-Zm/iI節段藉由5g/II連 接子加入而被修飾之。將所形成的DNA片段次選殖至一個 pCMV-81的址内，俾以生成哺乳動物表現質體（由芝 加哥大學的Graeme Bell博士所提供）。藉由使用磷酸鈣共_ 沉澱法（1)來轉染至CHO-K1細胞（ATCC)内而得到一個安 定地表現sst!受體之選殖的細胞株。質體pRSV-ne〇 (AtcC) 被包含之以作為一個可選擇的標記。於含有〇 ·5 mg/ml的 G418之RPMI 1640培養基内篩選出選殖的細胞株。予以環 早株化並擴增為培養物。 人類ssh生長激素釋放抑制因子受體基因，其被分離 成為一個1.7Kb 5_//1-所以111基因組DNA片段並被次選 殖至質體載體pGEM3Z (Promega)内，係由G. Bell博士（芝 加哥大學）所慷慨提供的。哺乳動物細胞表現載體係藉由將 該1.7Kb 5謂//1-//^^/111片段嵌入至質體pCMV5中之可相 谷核酸内切限制酶址内來構建。藉由使用填酸鈣共_沉澱法 -36- 本紙張尺度適用中國國家標準（CNS) A4規格（21〇><297公釐） (請先閲讀背面之注意事項再填寫本頁) •訂— :馨- 1236477 A7 B7 五、發明説明（34 ) (1)來轉染至C Η 0 - K1細胞内，而得到一個選殖細胞株。納 入質體pRSV-neo，以作為一個可選擇的標記。 (請先閲讀背面之注意事項再填寫本頁) 將人類sst3受體基因選殖成為一個基因組片段，而完 整的編碼序列被包含在一個2.4 Kb 片段 内。哺乳動物細胞表現載體pCMV_h3係藉由在兩端之修飾 以及加入五連接子後將一個2.0 Kb 片段插 入至pCMV載體之五址内來構建。藉由使用磷酸鈣共· 沉澱法來轉染至CHO-K1細胞（ATCC)内，而得到一個安定 地表現sst3受體之選殖的細胞株。納入質體pRSV-neo，以 作為一個可選擇的標記。於含有0.5 mg/ml的G418之RPMI 1640培養基内篩選出選殖的細胞株。予以環單株化並擴增 為培養物。 人類sst4受體表現質體PCMV-HX係由Graeme Bell博 士（芝加哥大學）所提供。該質體含有編碼人類sst4受體之 1.4 Kb 基因組DNA片段、456 bp的5’-未轉譯區域 以及200七？的3，-未轉譯區，殖入於？〇]^¥-11乂的1^1/五^7?1 址内。藉由使用磷酸鈣共-沉澱法來轉染至CHO-K1細胞 (ATCC)内，而得到一個安定地表現sst4受體之選殖的細胞 株。納入質體pRSV-neo，以作為一個可選擇的標記。於含 有0.5 mg/ml的G418之RPMI 1640培養基内篩選出選殖的 細胞株。予以環單株化並擴增為培養物。 人類sst5受體基因係藉由PCR並使用一個；I基因組純 株作為一個模版來獲得，且係由G. Bell博士（芝加哥大學） 所慷慨提供的。所形成的1.2 Kb的PCR片段含有21個鹼基 -37- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 A7 _B7__ 五、發明説明（35 ) 對之5’-未轉譯區域、整個編碼區域以及55 bp的3’-未轉譯 區。將該純株嵌入至質體pBSSK(+)之五址内。將該嵌 入物予以回收，而成為一個β7/2ί/ΙΙΙ-ΖΖ^Ι片段，以供次選殖 至pCVM5哺乳動物表現載體内。藉由使用磷酸鈣共-沉澱法 來轉染至CH0-K1細胞（ATCC)内，而得到一個安定地表現 sst5受體之選殖的細胞株。納入質體pRSV-neo (ATCC)，以 作為一個可選擇的標記。於含有0.5 mg/ml的G418 (Gibco) 之RPMI 1640培養基内篩選出選殖的細胞株。予以環單株 化並擴增為培養物。 將安定地表現人類sst受體之CH0_K1細胞培養於含有 10%胎牛血清與0.4 mg/ml的吉能提辛（geneticin)之RPΜI 1640培養基内。以0·5 mM EDTA來收集細胞，並於大約4 。(：下於500 g下予以離心歷時大約5分鐘。沉澱丸被再散浮 於50 mM Tris，pH 7.4内，並予以進行兩次在大約4°C下於 500 g下予以離心歷時大約5分鐘。藉由超音波振盪令細胞 分解，並於大約4°C下於39000 g下予以離心歷時大約10分 鐘。令沉澱丸再散浮於相同的緩衝液内，並於大約4°C下於 50000 g下予以離心歷時大約1〇分鐘，而將位在所形成的沉 澱丸内之胞膜儲存於-80°C下。 於聚丙烯96井盤内來進行[125I-Tyrn]SRIF-14結合之 競爭性抑制實驗，並做兩個重覆。細胞膜（10 gg的蛋白質/ 井）與[125I-Tyr"]SRIF-14 在 37°c 下被培育於 50 mM HEPES (pH 7.4)，0.2% BSA，5 mM MgCl2，200 KIU/ml抑肽酶 -38- 本紙張尺度適用中國國家標準（CNS) Α4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)Syndrome), gonodroptropinom, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, and polycystic Ovarian disease (polycystic ovary disease); used to treat various types of cancer, such as sacral adenocarcinoma, hepatocellular carcinoma, leukemia, meningioma, and cancer-related conditions, such as cancer cachexia; used to treat such as hypotension Symptoms, -32- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 1236477 V. Description of the invention (30) Such as low blood U and low blood μ after eating and panic attacks; gh secretory gonads Tumors and TSH-secreting adenomas. The activation of type 2 but not type 5 subtype receptors is related to the treatment of lactation; adenomas associated with leukosecretory adenomas. Symptoms associated with the activation of growth hormone release inhibiting factor subtypes are: inhibition of adiponin and / or glycemic hormone and especially diabetes, hyperlipidemia, insulin insensitivity, syndrome X, vascular disease , Proliferative retinopathy, d_ Phenomenon and kidney disease; inhibition of gastric acid secretion and especially peptic ulcers, fistulas of the intestine and skin and pancreas and skin, Dumping syndrome, diarrhea syndrome, acute or chronic pancreatitis, and Gastrointestinal hormone-secreting tumors; inhibition of angiogenesis, treatment of inflammatory diseases (such as arthritis); chronic allograft rejection; angioplasty; prevention of graft vessel and gastrointestinal bleeding. Somatropin release inhibitors can also be used to reduce a patient's weight. Therefore, the compound of the present invention can be used in the aforementioned method. Therefore, the present invention includes within its scope a pharmaceutical composition which comprises, as an active ingredient, at least one compound having the formula (I) and the formula (II) and associates it with a pharmaceutically acceptable carrier. The compounds of the present invention can be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously or subcutaneously, or implants), intranasally, vaginal, rectal, tongue It can be administered by a route of administration or topical administration, and can be formulated with a pharmaceutically acceptable carrier to provide a dosage form suitable for various administration routes. Solid dosage forms for oral administration include capsules, lozenges, pills, powders and granules. Among these solid dosage forms, the active compound -33- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 1236477 A7 V. Description of the invention (31 j substances are mixed with at least one emotional Pharmaceutically acceptable carriers, such as saccharose lactose or melon powder. These dosage forms may also contain additional substances which may be used in general in addition to the inert dilutions known, such as lubricants (such as hard Sodium fatty acid). In the case of capsules, tablets, and pills, this formula can also include buffering agents. Rotations and pills can be additionally prepared with an enteric coating. Liquid dosage forms for oral administration include Pharmaceutically acceptable emulsions, solutions, suspensions, polysaccharides, and diluents containing inert diluents commonly used in the art. In addition, in addition to these inert diluents, the composition of this case may also contain adjuvants such as wetting agents, Emulsifiers and flocculants), and flavoring, flavoring and flavoring agents. Preparations for parenteral administration according to the invention include sterile aqueous or non-aqueous solutions, suspensions or emulsions Non-aqueous solvents or vehicles include glycerol, polyethylene glycol, vegetable oils (such as olive oil and corn oil), gelatin, and injectable organic esters (such as ethyl oleate). These dosage forms can also contain Adjuvants, such as preservatives, humectants, emulsifiers and dispersants. These " bacterial agents, such as' by passing through a bacteria retention device, will be incorporated into the aseptic treatment agent to the composition Within the object, Xingchang radiation irradiates the composition, or heats the composition. These can also be caused to be in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable before use The composition for rectal or vaginal administration is preferably a test agent, which may contain excipients in addition to the active substance, such as cocoa butter or test agent 0-34 -......... · … 丨 (Please read the notes on the back before filling this page) Order ...------------- This paper size is applicable (CNS) A4 ^ (210X297 ^ 7 1236477 A7 ----- ------ B7__ V. Description of the invention (32) '' 'T, π or sublingual composition for medicinal use can also use this It is prepared using standard excipients known in the art. Furthermore, the compounds of the present invention having formulae (1) and (II) can be administered as a sustained release composition, such as those described in the following patents. United States Patent No. 5,672,659 teaches a sustained-release composition containing a bioactive agent and a polyester. US Patent No. 5,595, teaches a sustained-release composition containing a bioactive agent in a gelable form. September 1997 U.S. Patent Application No. 08 / 929,363 filed on the 9th teaches a polymerizable sustained-release composition containing a bioactive agent and polyhexamine (chhosan). In ^ such as year 丨 丨 month! U.S. Patent Application Serial No. 08 / 740,778, filed today, teaches a sustained release composition comprising a bioactive agent and a cyclodextrin. U.S. Patent Application No. 0,394, filed on January 29, 1998 teaches an absorbable sustained release composition containing a bioactive agent. The teachings of the aforementioned patents and applications are incorporated herein as reference materials. '' In general, the effective dose of a compound of the present invention having Formula ⑴ and Formula (π) in one of the compositions of this case can be varied; however, it is necessary that the amount of the active ingredient is such that a suitable Dosage form. The selected dose depends on the desired therapeutic effect, the route of administration and the duration of the treatment. This factor is within the scope of knowledge of those skilled in the art. Generally, a dose level of between 0.0001 and 100 mg / kg body weight per day is administered to humans and other animals (such as mammals). A preferred dosage range is from 0.01 to 100 ⑺ "body weight per day, which can be divided into a single dose1 or divided into several doses for administration. -35- This paper size depends on Zhongguanxianjia (⑽) A4 specifications (210X297 male & '" ~ " ------------------- ί equipment-(Dream first read the precautions on the back before filling this page) Order — 1236477 A7 _____B7 _ V. Description of the Invention (33) The compounds of the present invention can be evaluated for their ability to bind to growth hormone release inhibitor subtype receptors based on the following analysis. Human growth hormone release inhibitor subtype receptor binding studies: A compound for The affinity of human growth hormone release inhibitor subtype receptors 1 to 5 (ssti, sst2, sst3, sst4, and sst5, respectively) was determined by measuring [125I-Tyrn] SRIF-14 binding to CH0-K1 transfected cells The inhibitory effect was evaluated. The human SSt! Receptor gene was cloned into a genomic fragment. A 5'-untranslated region containing 100 bp, an entire coding region of 1.17 Kb, and a 3'-untranslated region of 230 bp The 1.5 Kb PwI-Zm / iI segment of the region was modified by the addition of a 5g / II linker The resulting DNA fragment was sub-selected into a pCMV-81 site to generate mammalian plastids (provided by Dr. Graeme Bell of the University of Chicago). By using the calcium phosphate co-precipitation method (1 ) To transfect into CHO-K1 cells (ATCC) to obtain a selected cell line stably expressing the sst! Receptor. The plastid pRSV-neO (AtcC) was included as a selectable marker. The selected cell lines were selected in RPMI 1640 medium containing G418 at 0.5 mg / ml. The cells were early planted in the ring and expanded into cultures. The human ssh growth hormone release inhibitor receptor gene was isolated into A 1.7Kb 5 _ // 1-so 111 genomic DNA fragment was sub-selected into the plastid vector pGEM3Z (Promega) and was generously provided by Dr. G. Bell (University of Chicago). The mammalian cell expression vector was borrowed The 1.7Kb 5 // 1-// ^^ / 111 fragment was embedded in the phase-restrictive endonuclease restriction enzyme site in pCMV5. By using a calcium-acid co-precipitation method -36 -This paper size applies Chinese National Standard (CNS) A4 (21〇 > < 297) ) (Please read the notes on the back before filling this page) • Order —: Xin-1236477 A7 B7 V. Description of the invention (34) (1) Transfected into C Η 0-K1 cells to get a colony Cell line. Incorporate pRSV-neo as a selectable marker. (Please read the notes on the back before filling out this page.) The human sst3 receptor gene is cloned into a genomic fragment, and the complete coding sequence is contained in a 2.4 Kb fragment. The mammalian cell expression vector pCMV_h3 was constructed by modifying the two ends and adding a five-linker to insert a 2.0 Kb fragment into the five site of the pCMV vector. By using calcium phosphate co-precipitation method to transfect into CHO-K1 cells (ATCC), a selected cell line stably expressing the sst3 receptor was obtained. Incorporate pRSV-neo as a selectable marker. The selected cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml G418. The loop was singulated and expanded into a culture. The human sst4 receptor-representing plastid PCMV-HX was provided by Dr. Graeme Bell (University of Chicago). The plastid contains a 1.4 Kb genomic DNA fragment encoding the human sst4 receptor, a 456 bp 5'-untranslated region, and 200? 3, -Untranslated region, colonized in? 〇] ^ ¥ -11 乂 within 1 ^ 1 / Five ^ 7? 1. By using calcium phosphate co-precipitation method to transfect into CHO-K1 cells (ATCC), a selected cell line stably expressing the sst4 receptor was obtained. Incorporate pRSV-neo as a selectable marker. The selected cell lines were selected in RPMI 1640 medium containing G418 at 0.5 mg / ml. The loops were singulated and expanded into cultures. The human sst5 receptor gene was obtained by PCR and used one; the I genome strain was obtained as a template and was generously provided by Dr. G. Bell (University of Chicago). The formed 1.2 Kb PCR fragment contains 21 bases-37- This paper is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 1236477 A7 _B7__ V. Description of the invention (35) 5'-untranslated Region, the entire coding region, and a 55 bp 3'-untranslated region. The pure plant was inserted into the five sites of pBSSK (+). The insert was recovered to form a β7 / 2ί / ΙΙΙ-ZZ ^^ fragment for secondary selection into the pCVM5 mammalian expression vector. By using calcium phosphate co-precipitation method to transfect into CH0-K1 cells (ATCC), a selected cell line stably expressing the sst5 receptor was obtained. Incorporate pRSV-neo (ATCC) as a selectable marker. The selected cell lines were selected in RPMI 1640 medium containing G418 (Gibco) at 0.5 mg / ml. The loops were singulated and expanded into cultures. CH0_K1 cells stably expressing the human sst receptor were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 0.4 mg / ml geneticin. Cells were harvested with 0.5 mM EDTA, and the cells were collected at approximately 4%. (: Centrifuge at 500 g for about 5 minutes. The pellets were re-suspended in 50 mM Tris, pH 7.4, and centrifuged twice at about 4 ° C at 500 g for about 5 minutes. The cells were decomposed by ultrasonic vibration and centrifuged at 39,000 g at about 4 ° C for about 10 minutes. The pellets were re-suspended in the same buffer, and at 50000 at about 4 ° C Centrifuge at g for about 10 minutes, and store the cell membrane in the formed pellet at -80 ° C. [125I-Tyrn] SRIF-14 binding was performed in a polypropylene 96-well plate. Competitive inhibition experiments and two replicates. Cell membrane (10 gg protein / well) and [125I-Tyr "] SRIF-14 were incubated at 37 ° C in 50 mM HEPES (pH 7.4), 0.2% BSA , 5 mM MgCl2, 200 KIU / ml aprotinin-38- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

、τ· 1236477 A7 B7___ 五、發明説明（36 ) (Trasylol)，0.02 mg/ml桿菌肽以及0·02 mg/ml苯基曱基磺 醯氟内，歷時60分鐘。 被結合的與游離的[l25l-Tyrll]SRIF-14係藉由使用 Filtermate 196 (Packard)細胞收穫器’而經由預次泡過〇·1 %聚乙烯亞胺（P.E.I.)之GF/C玻璃纖維過濾盤（Unifilter， Packard)來予以立即過滤。過滤器於大約C下以50 mM HEPES予以清洗歷時大約4秒，並使用Packard ToP計數器 來分析放射活性。 專一性結合量係藉由從總結合量中扣除掉非專一性 結合量（在有10 μΜ SRIF-14之存在下）來獲得。結合數據藉 由電腦協助的非線性迴歸分析（MDL)與抑制常數（Kl)數值 來分析之。 要決定本發明之化合物是否為一同效劑或一拮抗劑 係藉由下列分析。 功能性分析：cAMP胞内生成之抑制： 將會表現人類生長激素釋放抑制因子亞型受體之 CH0-K1細胞接種於24-井組織培養多井盤内位於加有10 % FCS 與 0.4 mg/ml吉能提辛（geneticin)之 RPMI 1640培養基 中。在實驗前一天予以更換培養基。 處於105細胞/井之量的CH0-K1細胞使用含0.2% BSA 並添加有0.5 mM (1) 3-異丙基-1·甲基黃°票°令（IBMX)之新 鮮RPMI予以清洗兩次，並將之培育於約37°C下，歷時大約 5分鐘。 春環狀腺苷單磷酸（AMP)生成之激發細藉由大約於 -39- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)Τ · 1236477 A7 B7___ V. Description of the invention (Trasylol), 0.02 mg / ml bacitracin and 0.02 mg / ml phenylfluorenylsulfonium fluoride, which lasted 60 minutes. The combined and free [l25l-Tyrll] SRIF-14 was GF / C glass fiber pre-soaked through 0.1% polyethyleneimine (PEI) by using Filtermate 196 (Packard) cell harvester Filter disc (Unifilter, Packard) to filter immediately. The filters were washed at approximately C with 50 mM HEPES for approximately 4 seconds, and the Packard ToP counter was used to analyze radioactivity. Specific binding was obtained by subtracting non-specific binding from the total binding (in the presence of 10 μM SRIF-14). The data were analyzed by computer-assisted nonlinear regression analysis (MDL) and inhibition constant (Kl) values. The determination of whether a compound of the invention is a synergist or an antagonist is made by the following analysis. Functional analysis: Inhibition of cAMP intracellular production: CH0-K1 cells that will express human growth hormone release inhibitor subtype receptors will be seeded in 24-well tissue culture multiwell plates with 10% FCS and 0.4 mg / ml ginnitol (genetic) in RPMI 1640 medium. The medium was changed the day before the experiment. CH0-K1 cells at 105 cells / well were washed twice with fresh RPMI containing 0.2% BSA and added with 0.5 mM (1) 3-isopropyl-1 · methyl yellow ° Order ° (IBMX) And incubate at about 37 ° C for about 5 minutes. The stimulus for the generation of acyclic cyclic adenosine monophosphate (AMP) is approximately -39- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) )

1236477 A7 B7 五、發明説明（37 ) 37°C下加入1 mM佛斯寇林（forskolin，FSK)歷時大 約15-30分鐘。 鲁一個化合物之同效劑效用係藉由同時加入FSK (1 μΜ)、SRIF-14 (ΙΟ·12 Μ至 1(Γ6 M)以及一個測試化 合物（10_1() Μ至10_5 Μ)來測定。 • 一個化合物之拮抗劑效用係藉由同時加入FSK (1 μΜ)、SRIF-14(1至10 ηΜ)以及一個測試化合物 (1(Γ10 Μ至 10_5 Μ)來測定。 反應培養基被移除，並予以加入200 ml的0.1 N HC1。 CAMP係藉由使用放射免疫分析法（Kit FlashPlate SMP001A，New England Nuclear)來測定。 本發明之化合物可就阻斷鈉通道之活性來作測試。本 發明化合物展現出對藜蘆素-敏感的鈉通道之結合。 有關結合私序’參照例如J. B. Brown，Journal of Neuroscience色，2064-2070 (1986)，該文獻之之内容在此併 入本案已為參考。其等會阻斷大白鼠海馬的切片製品 (hippocampal slice preparations)内之藜蘆素-誘發的麩胺 酸釋出。此實驗之進行係根據M.J. Leach et al.，in1236477 A7 B7 V. Description of the invention (37) Add 1 mM forskolin (FSK) at 37 ° C for about 15-30 minutes. The synergistic effect of a compound is determined by the simultaneous addition of FSK (1 μM), SRIF-14 (10 · 12 M to 1 (Γ6 M) and a test compound (10_1 () M to 10_5 M). The antagonist effectiveness of a compound was determined by simultaneous addition of FSK (1 μM), SRIF-14 (1 to 10 ηM) and a test compound (1 (Γ10 Μ to 10_5 Μ). The reaction medium was removed and allowed to 200 ml of 0.1 N HC1 was added. CAMP was measured by using radioimmunoassay (Kit FlashPlate SMP001A, New England Nuclear). The compounds of the present invention can be tested for their activity to block sodium channels. The compounds of the present invention exhibited Verabin-sensitive sodium channel binding. For binding sequences, refer to, for example, JB Brown, Journal of Neuroscience, 2064-2070 (1986), the contents of which are incorporated herein by reference. Will block veratolin-induced glutamic acid release in hippocampal slice preparations of rats. This experiment was performed according to MJ Leach et al., In

Epilepsia 2_Z，490-497 (1986)以及 Stroke 24· 1063-1067 (1993)之一個使用外源性麩胺酸之改良。 本發明之化合物係依據下列程序與實施例來合成。 点-咔啉 四氫-/3 -咔琳 -40- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)Epilepsia 2Z, 490-497 (1986) and Stroke 24 · 1063-1067 (1993), an improvement using exogenous glutamic acid. The compounds of the present invention were synthesized according to the following procedures and examples. Dot-Carboline Tetrahydro- / 3-Carlin -40- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

1236477 A7 五、發明説明（381236477 A7 V. Description of Invention (38

一般程序：一個具有式U)之胺在大約20-80°C下，於 一有或無一酸之質子酸或非質子酸溶劑（較佳為氣仿與 TFA)内，以一醛予以處理歷時大約5_72小時。所形成之咔 啉之分離（得到有如一個非對映體異構物之混合物）可以藉 由水性混合並接而於矽膠上進行閃蒸層析法來達成，或藉 由於反應混合物内加入一種被擔載於諸如胺基甲基聚氣乙 烯樹脂之聚合物上之親核試劑（以截留過量之醛）並接而進 行過濾、’然後快速純化位在一石夕膠塾板上之所形成的殘餘 物來達成（使用 Alltech silica cartridge 以及 Alltech manifold) 〇 實施例1位在1，2,3,4-四氫-1-(4-甲氧基苯基）_3(S)-(4-苯基1H-咪唾 -2-基）-9H- %唆並[3，4-b],味之Ci處的非對映體異構物混 合物 -41- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 丨丨.裝- :«· 1236477 A7 B7 五、發明説明（39General procedure: An amine of formula U) is treated with an aldehyde in a protic or aprotic solvent (preferably aeroform and TFA) with or without an acid at about 20-80 ° C. It lasted about 5_72 hours. The separation of the formed carboline (to obtain a mixture like a diastereoisomer) can be achieved by aqueous mixing followed by flash chromatography on silica gel, or by adding a reaction mixture to the reaction mixture. A nucleophile carried on a polymer such as aminomethylpolyvinyl resin (to retain excess aldehyde) is then filtered, and then the residue formed on a stone capsule is quickly purified. (Alltech silica cartridge and Alltech manifold) are used to achieve this. Example 1 is located at 1,2,3,4-tetrahydro-1- (4-methoxyphenyl) _3 (S)-(4-phenyl 1H-imido-2-yl) -9H-% pyre [3,4-b], a mixture of diastereomers at Ci Ci -41- This paper is in accordance with China National Standard (CNS) A4 Specifications (210X297 mm) (Please read the precautions on the back before filling this page) 丨 丨. Packing:: «· 1236477 A7 B7 V. Description of the invention (39

(請先閲讀背面之注意事項再填寫本頁) 乙基]-)-4-苯基-1H-咪唾（1〇〇 mg，1當量）溶液予以連續地加 入茴香醛（80 mL，2當量）與TFA (256 mL，10當量）。在於大 約20°C下攪拌大約兩天之後，混合物於減壓下予以濃縮， 而將殘餘物溶於THF (5 mL)内。加入胺基甲基聚氣乙烯樹 脂（Novabiochem，填載=1.2 mmol/g，5 50 mg，2 當量），並 於大約2 0 C下攪拌混合物過夜且過滤之。接而於減壓下濃 縮過遽液，並繼之措由在一碎膠塾板（Alltech silica cartridges)之快速過濾以及使用乙酸乙酯作為洗提液來行 純化，而獲得呈一非對映異構物混合物之四氫-石-咔啉 (65 :35)(產率=78%)。 NMR 400 MHz, CDC13): 12.2 (m, 1H5 NH)? 7.77-6.83 (m，15H，Harom，NH)，5.29, 5.17 (2s，1H，HJ，4.42 (m，1H， H3)，3.82, 3.78 (2s，3H，OCH3)，3.49 (m，1H，H4)，3.17 (m， 1H，H4，），1.90 (s，1H，NH)。LCIMS :計算的MW = 420.51， m/z= 421.05 (M+H)，m/z= 419.07 (M-H)。 -42. 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 A7 ________B7 五、發明説明（40 ) 實施例2 - 下列化合物可以類似於實施例1中所述之製程，使用 合適的起始材料來製備之，該等起始材料可獲自於商業來 源或是依據熟習此項技術人士所詳知的方法來合成之或是 如本文中所教示的來製備之。因此，如下所示的…與…之 每一組合被合成或可被合成之，因此，實施例之數目被乘 倍數地計算[R2 (21個取代基）][R5 (62個取代基）]二13〇2。 R2(Please read the precautions on the reverse side before filling out this page) Ethyl]-)-4-phenyl-1H-imidazole (100 mg, 1 equivalent) solution was continuously added with anisaldehyde (80 mL, 2 equivalents) ) With TFA (256 mL, 10 equivalents). After stirring for about two days at about 20 ° C, the mixture was concentrated under reduced pressure, and the residue was dissolved in THF (5 mL). Aminomethylpolyethylene resin (Novabiochem, loading = 1.2 mmol / g, 5 50 mg, 2 eq.) Was added, and the mixture was stirred at about 20 C overnight and filtered. The concentrated mash was then concentrated under reduced pressure, followed by rapid filtration on a crushed gel cartridge (Alltech silica cartridges) and purification using ethyl acetate as the eluent to obtain a diastereomer. Tetrahydro-stone-carboline (65:35) as a mixture of isomers (yield = 78%). NMR 400 MHz, CDC13): 12.2 (m, 1H5 NH)? 7.77-6.83 (m, 15H, Harom, NH), 5.29, 5.17 (2s, 1H, HJ, 4.42 (m, 1H, H3), 3.82, 3.78 (2s, 3H, OCH3), 3.49 (m, 1H, H4), 3.17 (m, 1H, H4,), 1.90 (s, 1H, NH). LCIMS: Calculated MW = 420.51, m / z = 421.05 ( M + H), m / z = 419.07 (MH). -42. This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 1236477 A7 ________B7 V. Description of the invention (40) Example 2-The following compounds It can be prepared similarly to the process described in Example 1 using suitable starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or It is prepared as taught herein. Therefore, each combination of ... and ... as shown below is synthesized or can be synthesized, and therefore, the number of embodiments is multiplied by [R2 (21 substituents )] [R5 (62 substituents)] 1320. R2

R2: α。、 ^>rVxi -43- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)R2: α. , ^ ≫ rVxi -43- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

1236477 A7 B7 五、發明説明（41 )1236477 A7 B7 V. Description of the invention (41)

(請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page)

本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 A7 B7 五、發明説明（42 ^9 BrThis paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 1236477 A7 B7 V. Description of the invention (42 ^ 9 Br

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^j〇^ j〇

JD/OX) \Α. 〆 (請先閲讀背面之注意事項再填寫本頁)JD / OX) \ Α. 〆 (Please read the notes on the back before filling this page)

Ν -取代的四氫yS_ 口卡琳 R2Ν-Substituted tetrahydroyS_ Carlin R2

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N, HN, H

、R4 45- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 A7 -— _ B7_ 五、發明説明（43 ) 一般程序：一個具有式（b)之化合物可在大約20-70°C 下，於非質子酸溶劑内與異氰酸鹽、異硫氰酸鹽、N_琥珀 醯亞胺基胺基甲酸酯、醯基氣或經活化的羧酸起反應歷時 2-1 8小時。所形成的衍生物之分離可藉由蒸發混合物並繼 之於矽膠上進行閃蒸層析法來達成，或於反應混合物内加 入一種被擔載於諸如胺基曱基聚氣乙烯樹脂或硫代曱基聚 氯乙烯樹脂之聚合物上之親核試劑（以截留過量之醛）並接 而進行過濾來達成。 對於經保護的鹼性衍生物（R4=(CH2)nNHBoc)，對應之 去保護的化合物（R4=(CH2)nNH2)之獲得係藉由在酸性條件 (DCM/TFA 10%)下處理N-保護的化合物。 實施例1304 位在1，2,3,4-四氫-1-(4-曱氧基苯基）-2 [(苯基胺基）幾 基]-3(S)-(‘苯基-IH-咪唑-2基）-9H-吡啶並[3,4-b] i嗓之C! 處的非對映體異構物混合物 (請先閲讀背面之注意事項再填寫本頁) •、可|, R4 45- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1236477 A7-_ B7_ V. Description of the invention (43) General procedure: A compound with formula (b) can be used in about 20- Reaction at 70 ° C with isocyanate, isothiocyanate, N-succinimide iminocarbamate, amidine gas or activated carboxylic acid in aprotic acid solvent for 2- 18 hours. Isolation of the formed derivatives can be achieved by evaporating the mixture followed by flash chromatography on silica gel, or adding a reactive vinyl chloride resin or thiol supported on the reaction mixture, such as an aminofluorene-based polyethylene gas. The nucleophile on the polymer of fluorene-based polyvinyl chloride resin (to retain excess aldehyde) is then filtered to achieve it. For protected basic derivatives (R4 = (CH2) nNHBoc), the corresponding deprotected compound (R4 = (CH2) nNH2) is obtained by treating N- under acidic conditions (DCM / TFA 10%) Protected compounds. Example 1304 Positioned at 1,2,3,4-tetrahydro-1- (4-methoxyoxyphenyl) -2 [(phenylamino) hexyl] -3 (S)-('phenyl- IH-imidazol-2-yl) -9H-pyrido [3,4-b] i diastereoisomeric mixtures at C! (Please read the precautions on the back before filling this page) •, may |

對一個配於氯仿（700 mL)内之ι，2,3,4-四氫_1-(4-曱氧 基苯基）-3(S)-(4-苯基1H-17米唾-2 -基）-9Η- σ比咬並[3,4-b]弓| -46- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐〉 1236477 A7 ____B7_ 五、發明説明（44 ) (請先閲讀背面之注意事項再填寫本頁) 哚的非對映異構物混合物溶液，予以加入苄基異氰酸酯。 混合物於大約20°C下予以攪拌過夜並接而以氣仿（2 mL)來 稀釋。將胺基甲基聚氣乙稀樹脂（Novabiochem，填載=1.2 mmol/g，198 mg，2當量）加入至混合物内。於大約2〇。〇下振 盪大約15小時後，過濾混合物並於減壓下濃縮之，以生成 標題化合物（60 mg，92%產率）。7VM7? (b，400 MHz，CDC13) 5 : 9.2-6.7 (m，22H，arom· Η，ΝΗ)，6·25 (m，1H，HD，5·80 (m，1H，H3)，4.52-4.32 (m，2H，C//2Ph)，3.81-3.28 (m，5H， OCH3, H4, H4.)、LC/MS :計算的 MW : 553.66, m/z = 554.2 (M+H)。 實施例1305-1332 下列化合物可以類似於實施例1304中所述之製程，使 用合適的起始材料來製備之，該等起始材料可獲自於商業 來源或是依據熟習此項技術人士所詳知的方法來合成之或 是如本文中所教示的來製備之。因此，如下所示的以4與R5 之每一組合被合成或可被合成之，因此，實施例之數目被 乘倍數地計算[R4 (9個取代基）][R5 (3個取代基）]==27。 -47- 本紙張尺度適用中國國家標準（CNS) A4規格（210χ297公釐） 1236477 A7 B7 五、發明説明（45 )For one, 1,2,3,4-tetrahydro_1- (4-methoxyphenyl) -3 (S)-(4-phenyl 1H-17 Misaline) formulated in chloroform (700 mL) 2 -base) -9Η- σ specific bite [3,4-b] bow | -46- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 1236477 A7 ____B7_ V. Description of the invention (44) (Please read the precautions on the back before filling this page) Add benzyl isocyanate to the solution of the diastereomer mixture of indole. The mixture is stirred at about 20 ° C overnight and then aerated with (2 mL) To dilute. Aminomethylpolyethylene resin (Novabiochem, loading = 1.2 mmol / g, 198 mg, 2 equivalents) was added to the mixture. After shaking for about 15 hours at about 20.0, the mixture was filtered And concentrated under reduced pressure to give the title compound (60 mg, 92% yield). 7VM7? (B, 400 MHz, CDC13) 5: 9.2-6.7 (m, 22H, arom ··, ΝΗ), 6 · 25 (m, 1H, HD, 5.80 (m, 1H, H3), 4.52-4.32 (m, 2H, C // 2Ph), 3.81-3.28 (m, 5H, OCH3, H4, H4.), LC / MS: Calculated MW: 553.66, m / z = 554.2 (M + H). Examples 1305-1332 The following compounds It can be prepared similar to the process described in Example 1304 using suitable starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or It was prepared as taught herein. Therefore, each combination of 4 and R5 as shown below can be synthesized or can be synthesized, so the number of examples is calculated by a multiple of [R4 (9 substitutions Base)] [R5 (3 substituents)] == 27. -47- This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 1236477 A7 B7 V. Description of the invention (45)

一般程序：一個具有式（c)之化合物可在20-80°C下， 使用位在一非質子酸溶劑（諸如甲苯或二甲苯）内之碳上鈀 或DDQ、位在一質子酸溶劑内之鎘酸、在THF内之ΚΜη04 -48- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)General procedure: A compound of formula (c) can be placed in a protic acid solvent using palladium or DDQ on carbon in an aprotic acid solvent (such as toluene or xylene) at 20-80 ° C. Cadmium acid, KMη04 -48 in THF- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

1236477 A7 _______B7 _ 五、發明説明（46 ) 或在一非質子酸溶劑（較佳為氣仿）内内之二氧化鎂，被氧 化歷時2-48小時而成為對應之完全芳香化的石-咔琳。 (請先閱讀背面之注意事項再填寫本頁) 實施例 1333 1-丁基-3-(4-苯基-1H-咪唑-2基）-9H-吡啶並[3,4-b]，哚：1236477 A7 _______B7 _ V. Description of the invention (46) or magnesium dioxide in an aprotic acid solvent (preferably aerobic) is oxidized for 2-48 hours to become the corresponding fully aromatic stone-Ka Lynn. (Please read the notes on the back before filling this page) Example 1333 1-Butyl-3- (4-phenyl-1H-imidazol-2yl) -9H-pyrido [3,4-b], indole :

1，2,3,4-四氫-1-丁基-3(11)-(4-苯基-111-咪唑-2基）-911-口比°定並[3,4-b],啼（100 mg，1當量）與二氧化鎮（600 mg)之 一配於氣仿（7 mL)的混合物在大約40°C下被加熱歷時大約 3小時。混合物被冷卻至大約20°C並於CELITE®墊板上予 以過濾之。過濾液於減壓下被濃縮而生成相當量之完全芳 香化的/3 -咔啉（97 mg)。 NMR (lU9 400 MHz, CDC13)： 10.8 (s, 1H, NH)? 8.77-7.25 (m，11H，arom. H，NH)，3.07 (t，2H，3J = 8Hz，CH2)，1.85 (m，2H，CH2)，2.42 (m，2H，CH2)，0.91 (t，3H，3J = 8Hz， CH3)。LCIMS ··計算的 MW = 366.46, m/z = 367.19 (M+H)， m/z = 479.15 (M+TFA). -49- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 A7 _____B7_ 五、發明説明（47 ) (請先閲讀背面之注意事項再填寫本頁) 實施例 1334-1336 下列化合物可以類似於實施例1333中所述之製程，使 用合適的起始材料來製備之，該等起始材料可獲自於商業 來源或是依據熟習此項技術人士所詳知的方法來合成之或 是如本文中所教示的來製備之。1,2,3,4-tetrahydro-1-butyl-3 (11)-(4-phenyl-111-imidazol-2yl) -911-port ratio ° [3,4-b], A mixture of cryol (100 mg, 1 equivalent) and one of the dioxide (600 mg) in aeroform (7 mL) was heated at about 40 ° C for about 3 hours. The mixture is cooled to approximately 20 ° C and filtered on a CELITE® pad. The filtrate was concentrated under reduced pressure to give a considerable amount of fully aromatized / 3-carboline (97 mg). NMR (1U9 400 MHz, CDC13): 10.8 (s, 1H, NH)? 8.77-7.25 (m, 11H, arom. H, NH), 3.07 (t, 2H, 3J = 8Hz, CH2), 1.85 (m, 2H, CH2), 2.42 (m, 2H, CH2), 0.91 (t, 3H, 3J = 8Hz, CH3). LCIMS ·· Calculated MW = 366.46, m / z = 367.19 (M + H), m / z = 479.15 (M + TFA). -49- This paper size applies to China National Standard (CNS) A4 (210X297 mm) ) 1236477 A7 _____B7_ V. Description of the invention (47) (Please read the notes on the back before filling this page) Example 1334-1336 The following compounds can be similar to the process described in Example 1333, using appropriate starting materials As prepared, the starting materials can be obtained from commercial sources or synthesized in accordance with methods well known to those skilled in the art or prepared as taught herein.

實施例1337-1493 下列化合物可以類似於實施例1333中所述之製程，使 用合適的起始材料來製備之，該等起始材料可獲自於商業 來源或疋依據熟習此項技術人士所詳知的方法來合成之咬 是如本文中所教示的來製備之。實施例之數目被計算如下 -50- 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 A7 B7 五、發明説明（ 48 [R2 (4個取代基）][R5 (39個取代基）]=156Examples 1337-1493 The following compounds can be prepared similar to the process described in Example 1333 using suitable starting materials, which can be obtained from commercial sources or as detailed by those skilled in the art Known methods for synthesizing bites are prepared as taught herein. The number of examples is calculated as follows -50- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 1236477 A7 B7 V. Description of the invention (48 [R2 (4 substituents)] [R5 (39 Substituents)] = 156

本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1236477 A7 B7 五、發明說明（49 ) 實施例 1494 (lR)-l-(4,5-二甲基-1，3-噁唑-2基）-2-(1Η-吲哚-3基）_：[-乙胺 氯化氫 β^--- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 一個配於HCl/AcOEt IN (80ml)内之特-丁基 二甲基-1，3-噁唑-2 基）-2-(1Η-吲哚 -3-基） 乙基-胺基甲 酸酯（3g，8.4mmol)的溶液在室溫下攪拌歷時2.5小時。混 合物於減壓下予以濃縮，加入二乙基醚（l〇〇ml),並藉由 過濾來收集白色沉澱物，且使用二乙基醚予以清洗而提供 所欲產物之氣化氩鹽（2.4g)。熔點：172-174°C。 (3R)-1,1-二丁基-3-(4,5-二甲基-1,3-噁唑-2基）-2,3,4,9-四氫 咔啉氣化氫 -52- 訂· · •線·This paper size applies to China National Standard (CNS) A4 (210X297 mm) 1236477 A7 B7 V. Description of the invention (49) Example 1494 (lR) -l- (4,5-dimethyl-1,3-oxalate Azole-2yl) -2- (1Η-indole-3yl) _: [-ethylamine hydrogen chloride β ^ --- (Please read the precautions on the back before filling out this page) Employees ’Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs Print a tert-butyldimethyl-1,3-oxazole-2yl) -2- (1Η-indol-3-yl) ethyl-amine group in HCl / AcOEt IN (80ml) A solution of formate (3 g, 8.4 mmol) was stirred at room temperature for 2.5 hours. The mixture was concentrated under reduced pressure, diethyl ether (100 ml) was added, and a white precipitate was collected by filtration, and washed with diethyl ether to provide the vaporized argon salt of the desired product (2.4 g). Melting point: 172-174 ° C. (3R) -1,1-dibutyl-3- (4,5-dimethyl-1,3-oxazole-2yl) -2,3,4,9-tetrahydrocarboline gasification hydrogen- 52- Order · · · Line ·

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 3/1236477 A7 五、發明說明（5〇)This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 3/1236477 A7 V. Description of the invention (50)

「I"I

對一個配於異丙醇（20ml)内之（lR)-l-(4,6-二甲基· 1，3-噁唑-2-基）-2·(1Η-吲哚-3基）-1-乙胺氯化氫（l.2g> 3.6mmol)溶液予以加入5-壬嗣（3.1ml，20mmol)，並令思合 物回流歷時約24小時。溶劑於減壓下被蒸發，對殘餘物予 以加入水（20ml)繼之加入NAHC03 (10%)溶液直至達中性 pH值，接而加入乙酸乙酯（3x15ml)。在傾倒與萃取後，將 合併的有機萃取物以水（20ml)予以清洗，並於MgS04上乾 燥之。溶劑於減壓下被蒸發，而提供一藉由管柱層析法於 矽膠上使用乙酸乙酯/庚烷7··3作為洗提液來純化之油。所 形成之油被溶於乙酸乙酯（15ml)内，並於大約20°C下予以 緩慢地加入配於乙酸乙酯内之HC1溶液（1N)，以得到一個 沉澱物。散浮液予以攪拌數分鐘，並藉由過濾來收集沉澱 物，以二乙基醚予以清洗，並將之乾燥而提供如同氣化氫 鹽之0.14g的所欲產物。熔點：128-134°C。 實施例1495(311)-3-(4-苯基-111-咪唑-2基）-2,3,4,9-四氩-1|-苯甲醯基-螺 狀[1H-/S -咔啉·1，4’_哌啶]氣化氩 •53. 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------------裝--- 、清先閱讀背面之注意事項再填寫本頁} _νιό· 1236477 A7 ________ B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（51)(LR) -l- (4,6-dimethyl · 1,3-oxazol-2-yl) -2 · (1Η-indole-3yl) formulated in isopropanol (20ml) A solution of 1-ethylamine hydrogen chloride (1.2 g > 3.6 mmol) was added to 5-nonane (3.1 ml, 20 mmol), and the compound was refluxed for about 24 hours. The solvent was evaporated under reduced pressure, and the residue was added with water (20 ml) followed by a solution of NAHC03 (10%) until a neutral pH was reached, followed by ethyl acetate (3 x 15 ml). After decantation and extraction, the combined organic extracts were washed with water (20 ml) and dried over MgS04. The solvent was evaporated under reduced pressure to provide an oil purified by column chromatography on silica gel using ethyl acetate / heptane 7 · 3 as an eluent. The resulting oil was dissolved in ethyl acetate (15 ml) and slowly added to a solution of HC1 (1N) in ethyl acetate at about 20 ° C to obtain a precipitate. The suspension was stirred for several minutes, and the precipitate was collected by filtration, washed with diethyl ether, and dried to provide 0.14 g of the desired product as a hydrogenated hydrogen salt. Melting point: 128-134 ° C. Example 1495 (311) -3- (4-phenyl-111-imidazol-2yl) -2,3,4,9-tetraargon-1 | -benzylidene-spiral [1H- / S- Carboline · 1,4'_piperidine] Gasified argon • 53. This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -------------- ----- 、 Please read the notes on the back before filling in this page} _νιό · 1236477 A7 ________ B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of Invention (51)

對一個配於異丙醇（15ml)内之（1R)-2_(1H-吲哚-3基）· 1-(4-苯基-1H-咪唑-2基）-1-乙胺氣化氫（lg，2.65mmol)溶液 予以加入N-苯甲醯基-4-哌啶酮（2.64g，13mmol)。溶液予 以回流歷時大約1小時，並將之冷卻至大約20°C。溶劑於 減壓下被移除。殘餘物以二氣甲烷（3Oml)予以處理並於大 約20°C下攪拌歷時大約30分鐘。所形成的沉澱物藉由過濾 來收集，以二氣甲烷與二乙基醚予以清洗並將之乾燥，而 提供如同氯化氫鹽之1.2g的標題產物。熔點：240-244°C。 實施例1496 (3R)-3-(4-苯基-1H-咪唑-2基）-2,3,4,9-四氫-1，-(特-丁氧基 羰基）-螺狀[1H- /9 -咔啉-i，4，-哌啶] -54- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) ---— — — — — ^«1 — I I 1 I I I ' 1236477 A7 B7 五、發明說明（52(1R) -2_ (1H-indole-3yl) · 1- (4-phenyl-1H-imidazol-2yl) -1-ethylamine hydrogenated in isopropyl alcohol (15ml) (Lg, 2.65 mmol) was added to N-benzylidene-4-piperidone (2.64 g, 13 mmol). The solution was refluxed for approximately 1 hour and cooled to approximately 20 ° C. The solvent was removed under reduced pressure. The residue was treated with digas methane (30 ml) and stirred at about 20 ° C for about 30 minutes. The formed precipitate was collected by filtration, washed with digas methane and diethyl ether and dried to provide 1.2 g of the title product as a hydrogen chloride salt. Melting point: 240-244 ° C. Example 1496 (3R) -3- (4-phenyl-1H-imidazol-2yl) -2,3,4,9-tetrahydro-1,-(tert-butoxycarbonyl) -spiro [1H -/ 9 -Carboline-i, 4, -piperidine] -54- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) ---— — — — — ^ «1 — II 1 III '1236477 A7 B7 V. Description of the invention (52

N 〇人 H3C-^CH3 ch3 對一個配於異丙醇（210ml)内之（1R)-2_(1H-吲哚-3 基）-1-(4-苯基·1Η-味啥_2基）-1-乙胺氣化氫（14g，35mmol) 溶液予以加入1-特-丁氧基羰基-4-哌啶酮（35g, 170mmol)，而混合物予以回流大約2小時。溶劑於減壓下 被蒸發。對殘餘物予以加入水（150ml)繼之加入10% NaHC03溶液直至達中性pH值，並藉由乙酸乙酯（4X50ml) 予以萃取。將合併的有機萃取物以水（2x50ml)予以清洗， 並於MgSCU上乾燥之❶溶劑於減壓下被移除，而提供一在 二異丙基醚（150ml)時會固化之油》藉由過濾來收集沉澱 物’以二異丙基謎予以清洗並將之乾燥，而提供13.5g之 所欲產物。熔點：118-1200°C。 f施例1497 (3R)-3-(4-苯基-1H-咪唑-2基）-2,3,4,9-四氫-螺狀[111-沒-叶 琳-1，4、旅啶 -55- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------------^ — (請先閱讀背面之注意事項再填寫本頁) 訂·- i線- 1236477 A7 ——____ B7五、發明說明（53 )N 〇Human H3C- ^ CH3 ch3 to a (1R) -2_ (1H-indole-3yl) -1- (4-phenyl · 1Η- 味 什 _2yl) compound in isopropanol (210ml) ) -1-Ethylamine gasified hydrogen (14 g, 35 mmol) was added to 1-tetra-butoxycarbonyl-4-piperidone (35 g, 170 mmol), and the mixture was refluxed for about 2 hours. The solvent was evaporated under reduced pressure. To the residue was added water (150 ml) followed by 10% NaHC03 solution until a neutral pH was reached, and it was extracted with ethyl acetate (4 × 50 ml). The combined organic extracts were washed with water (2x50ml), and the hydrazone solvent dried on MgSCU was removed under reduced pressure to provide an oil that will solidify with diisopropyl ether (150ml). The precipitate was collected by filtration ', washed with diisopropyl puzzle and dried to provide 13.5 g of the desired product. Melting point: 118-1200 ° C. fExample 1497 (3R) -3- (4-phenyl-1H-imidazol-2yl) -2,3,4,9-tetrahydro-spiral [111- 没-叶 琳 -1, 4, Lu Pyridine-55- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -------------- ^ — (Please read the precautions on the back before filling in this Page) Order ·-i-line-1236477 A7 ——____ B7 V. Description of the invention (53)

經濟部智慧財產局員工消費合作社印製 將一個配於乙酸乙酯（400ml)内之（3R)-3-(4-苯基-1H-咪唑-2基）-2,3,4,9-四氫-1，-(特·丁氧基羰基）_螺狀[1H-点· 味琳-1，4匕旅咬]溶液以冰浴冷卻至大約〇°c並以以無水HC1 氣體流予以處理歷時大約2小時。溶劑於減壓下被移除而 提供一個半固體。使用丙酮來研製而得到一個白色固體， 藉由過滤予以收集並且用丙酿I與二乙基謎予以清洗3次。 氣化氩鹽以NaHC03 10%溶液予以轉化成自由鹼，而水層 部分以乙酸乙酯（3x50ml)來萃取。將合併的有機萃取物以 水（2x50ml)予以清洗，於MgS04上乾燥，將之過濾與蒸發 而提供l〇g之所欲產物。熔點：> 2500°C。 實施例 1498 (lR)-2-(l-苯並嗟吩-3基）-1-(4-苯基-1H-咪啥-2基）-1-乙胺 HC1 -56- 本紙張尺度適用中國國家標準（CNS)A4規烙（210 X 297公釐） ---I-----I I -----— — It —-------^ —^wi (請先閱讀背面之注意事項再填寫本頁) 1236477 A7 B7Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, (3R) -3- (4-phenyl-1H-imidazole-2yl) -2,3,4,9- Tetrahydro-1,-(te · butoxycarbonyl) _spiral [1H-point · Mirin-1,4 dagger bite] The solution was cooled in an ice bath to approximately 0 ° C and applied with an anhydrous HC1 gas stream. Processing took approximately 2 hours. The solvent was removed under reduced pressure to provide a semi-solid. Trituration with acetone yielded a white solid, which was collected by filtration and washed 3 times with Propanol I and Diethyl Enzyme. The vaporized argon salt was converted to a free base with a 10% solution of NaHC03, and the aqueous layer was partially extracted with ethyl acetate (3x50 ml). The combined organic extracts were washed with water (2x50 ml), dried over MgS04, filtered and evaporated to provide 10 g of the desired product. Melting point: > 2500 ° C. Example 1498 (lR) -2- (l-benzopyrene-3yl) -1- (4-phenyl-1H-micha-2yl) -1-ethylamine HC1 -56- Applicable to this paper China National Standard (CNS) A4 (210 X 297 mm) --- I ----- II ------- — It —------- ^ — ^ wi (Please read first Note on the back, please fill out this page) 1236477 A7 B7

CC

五、發明說明（54 ,HC1 一個配於 70ml的 IN HCl/AcOEt内之特-丁基（1)-2-(1-苯並噻吩-3基）-1-(4-苯基-1H-咪唑-2基）乙基胺基曱酸酯 (4g，9.5mmol)溶液被溫熱至大約5(TC歷時大約1小時。混 合物被濃縮並予以加入二乙基醚（50ml)。所形成的白色沉 澱物藉由過濾來收集並以二乙基醚予以清洗而提供所欲產 物之氣化氫鹽（3g)。熔點：190-192°C。 (3R)-3-(4-苯基-1H-咪唑-2基）-2,3,4,9-四氫 _lf-[N-(3-吐啶 基）碳硫醯胺]螺狀[lH-石-咔啉-1，4·-哌啶] . I-----I I I I ^ · I I (請先閱讀背面之注意事項再填寫本頁) 訂： I 1才 t L· L· 1V. Description of the invention (54, HC1 A t-butyl (1) -2- (1-benzothiophen-3yl) -1- (4-phenyl-1H- in 70 ml of IN HCl / AcOEt) A solution of imidazole-2yl) ethylaminophosphonate (4 g, 9.5 mmol) was warmed to about 5 (TC for about 1 hour. The mixture was concentrated and diethyl ether (50 ml) was added. The white formed The precipitate was collected by filtration and washed with diethyl ether to provide the gasified hydrogen salt (3g) of the desired product. Melting point: 190-192 ° C. (3R) -3- (4-phenyl-1H -Imidazol-2yl) -2,3,4,9-tetrahydro_lf- [N- (3-turidyl) carbathionamine] spiral [lH-stone-carboline-1,4 ·- Piperidine]. I ----- IIII ^ · II (Please read the precautions on the back before filling this page) Order: I 1 before t L · L · 1

對一個配於二氣甲烷（5ml)内之（3R)-3-(4-苯基-1Η-咪 •線· -57- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1236477 經濟部智慧財產局員工消費合作社印制农 A7 B7 五、發明說明（55) 唾-2基）-2,3,4,9-四氫-螺狀[iH-冷-咔啉哌啶](〇.38g， iOmmol)溶液予以加入3-吡啶基異硫氫酸酯（〇 136g， lOmmol)。混合物於大約2〇°c下予以攪拌歷時大約30分 鐘’而所形成的沉澱物藉由過濾來收集，並以二氯甲烷與 二乙基醚予以清洗，而提供〇 38g的所欲產物。熔點： 234-236°C。 實施例 1499 • (3r)-i，i-二丁基-3_(4-苯基一1H-味唑基）各四氫⑴ 苯並嘍吩並[2,3-c]^t咬For a (3R) -3- (4-phenyl-1Η-ami • line · -5 ·) formulated in digas methane (5ml), this paper size applies to China National Standard (CNS) A4 (210 X 297) 1236477 A7 B7 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (55) sal-2 base) -2,3,4,9-tetrahydro-spiral [iH-Cold-Carboline Pipe Pyridine] (0.38 g, 10 mmol) was added to 3-pyridyl isothiohydrogenate (0.136 g, 10 mmol). The mixture was stirred at about 20 ° C for about 30 minutes' and the formed precipitate was collected by filtration and washed with dichloromethane and diethyl ether to provide 0.38 g of the desired product. Melting point: 234-236 ° C. Example 1499 • (3r) -i, i-dibutyl-3_ (4-phenyl-1H-amizolyl), each tetrahydrofluorene, benzofluoreno [2,3-c] ^ t bite

對一個配於τι-丁醇（2〇ml)内之（lR)-2-(l-苯並噻吩-3 基）-1-(4-苯基-1H，咪唑-2-基）-1-乙胺（lg，2.5mmol)予以加 入5-壬闕（2.2ml，13mmol)，並令混合物回流過夜。溶劑於 減壓下被移除《對殘餘物予以加入水（15rnl)繼之加入1〇〇/0 NaHC〇3溶液直至達中性pH值，並藉由乙酸乙酯（3x2〇ml) 予以萃取。將合併的有機萃取物以水（2x10ml)予以清洗， 並於MgS〇4上乾燥以及過濾之〃溶劑於減壓下被蒸發，而 -58- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 997公釐） (請先閱讀背面之注意事項再填寫本頁)To (lR) -2- (l-benzothiophen-3yl) -1- (4-phenyl-1H, imidazol-2-yl) -1 in τι-butanol (20 ml) -Ethylamine (lg, 2.5 mmol) was added to 5-nonane (2.2 ml, 13 mmol) and the mixture was refluxed overnight. The solvent was removed under reduced pressure. The residue was added with water (15rnl) followed by a 100/0 NaHC〇3 solution until a neutral pH was reached and extracted with ethyl acetate (3x20ml). . The combined organic extracts were washed with water (2x10ml), dried over MgS04 and filtered. The solvent was evaporated under reduced pressure, and this paper size is in accordance with Chinese National Standard (CNS) A4 specifications 210 X 997 mm) (Please read the notes on the back before filling this page)

1236477 A7 B71236477 A7 B7

五、發明說明（5〇 提供一藉由管柱層析法於矽膠上使用乙酸乙酯/庚烷1:1作 為洗提液來純化之油。在移除溶劑後，對殘餘物予以加入 二異丙基醚。所形成的白色沉澱物被過濾並以二異丙基醚 來清洗，而提供o.lg的標題化合物。熔點：198-200°C。 實施例 1500 (3尺)-1，1-二丁基-3-(4-苯基-111-咪唑-2基）-2,3,4,9-四氫-IH-yS -咔啉延胡索酸鹽V. Description of the invention (50 provides an oil purified by column chromatography on silica gel using ethyl acetate / heptane 1: 1 as an eluent. After the solvent is removed, the residue is added to two Isopropyl ether. The white precipitate formed was filtered and washed with diisopropyl ether to provide the title compound at 0.1 mg. Melting point: 198-200 ° C. Example 1500 (3 feet) -1, 1-dibutyl-3- (4-phenyl-111-imidazol-2yl) -2,3,4,9-tetrahydro-IH-yS-carboline fumarate

令一個（1R)-2_(1H-吲哚-3基）-1-(4-苯基-1H-咪唑-2 基）-1_乙胺氣化氫（10g，33mmol)、η-丁醇（150ml)與5-壬嗣 (23.44g，165mmol)之混合物回流歷時大約4小時，並接而 使用一個Dean-Stark裝置來移除10ml的η- 丁醇。在回流歷 時大約又再兩個小時後，將混合物加熱至大約l〇〇°C過夜。 將溶劑蒸發掉，並令所形成的殘餘物在乙酸乙酯（100ml〕 與10% NaHC03溶液（50ml)之間作分部分離。在傾倒後， 有機層以10% NaHC03溶液（50ml)與水來清洗並於MgSCX 上乾燥。蒸發掉溶劑而提供一個栋色的殘餘物，且藉由於 石夕膠上進行閃蒸層析法（洗提液：二氣甲烷/乙酸乙酯9:1: 一-59- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） , ----I I I I ^ · I I I I--- (請先閱讀背面之注意事項再填寫本頁) 1236477 A7 B7 五、發明說明（57) (請先閱讀背面之注意事項再填寫本頁) 予以純化之。收集純質的分離部分並將之濃縮，而在以二 異丙基醚清洗後得到如同自由鹼之3.6g的標題化合物。熔 點：160-162°C。 將自由驗（1.3g，3 mmol)溶於丙酮（5ml)内。予以加入 延胡索酸（448mg，3mmol)。將混合物溫熱至大約50°C以得 到一個溶液。在靜置過夜後，白色晶體出現《予以加入二 乙基醚（20ml)，並藉由過濾來收集經過乾燥的化合物 (1.05g)。熔點：168-170°C。 實施例1501 (3R)_3-(4-苯基-1H-咪唑-2基）-2,3,4,9-四氩-螺狀[ΙΗ-点-咔 啉-1，1-環庚基]Let a (1R) -2_ (1H-indole-3yl) -1- (4-phenyl-1H-imidazol-2yl) -1-ethylamine hydrogenated gas (10 g, 33 mmol), η-butanol A mixture of (150 ml) and 5-nonazine (23.44 g, 165 mmol) was refluxed for about 4 hours, and then a Dean-Stark device was used to remove 10 ml of n-butanol. After about two more hours at reflux, the mixture was heated to about 100 ° C overnight. The solvent was evaporated off and the resulting residue was separated between ethyl acetate (100 ml) and 10% NaHC03 solution (50 ml). After pouring, the organic layer was mixed with 10% NaHC03 solution (50 ml) and water. To wash and dry on MgSCX. Evaporate off the solvent to provide a colorless residue, and perform flash chromatography on Shi Xijiao (eluent: methane / ethyl acetate 9: 1: 1 -59- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm), ---- IIII ^ · III I --- (Please read the precautions on the back before filling this page) 1236477 A7 B7 V. Description of the invention (57) (Please read the notes on the back before filling this page) to purify it. Collect the pure separated part and concentrate it, and get the same as free base after washing with diisopropyl ether. 3.6 g of the title compound. Melting point: 160-162 ° C. Dissolve the free test (1.3 g, 3 mmol) in acetone (5 ml). Add fumaric acid (448 mg, 3 mmol). Warm the mixture to about 50 ° C to get a solution. After standing overnight, white crystals appeared Ether (20 ml), and the dried compound (1.05 g) was collected by filtration. Melting point: 168-170 ° C. Example 1501 (3R) _3- (4-phenyl-1H-imidazole-2yl) -2,3,4,9-tetraargon-spiro [ΙΗ- 点 -carboline-1,1-cycloheptyl]

經濟部智慧財產局員工消費合作社印？衣 對（0.75g，2.5mmol)之（lR)-2-(lH-吲哚-3 基）-1-(4-苯 基-1H-咪唑-2基）-1-乙胺予以加入20ml的1,2-二氣乙烷、 三氧乙酸（2ml，25mmol)與環庚_ (560mg，5mmol)。將混合 物回流大約4小時。又再加入三氟乙酸（lml)與環庚酮 (560mg)並繼績回流歷時大約4小時。溶劑於減壓下被移 •60- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1236477 A7 --- - β" ! - ----- 五、發明說明（58 ) 除。對殘餘物予以加入20ml的乙酸乙酯與1〇% NaHC03溶 液。在傾倒後，有基層以水予以清洗，並於MgS04上乾燥。 蒸發掉溶劑而提供一個殘餘物，且藉由於矽膠上進行閃蒸 層析法（洗提液：庚烷/乙酸乙酯3:7)予以純化之。收集純 質的分離部分並將之濃縮，而得到80g的標題化合物《熔 點：208_210°C。 實施例1502 (3R)-3-(4-苯基-1H-咪唑-2-基）_2,3,4,9-四氫-1丨-[3-(4甲基 苯基）-1-丙醯基]螺狀[IH-)S -咔啉-1，4，-哌啶]Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs? (0.75 g, 2.5 mmol) of (lR) -2- (lH-indole-3yl) -1- (4-phenyl-1H-imidazol-2yl) -1-ethylamine was added to 20 ml of 1,2-Digas ethane, trioxoacetic acid (2 ml, 25 mmol) and cycloheptyl (560 mg, 5 mmol). The mixture was refluxed for approximately 4 hours. Trifluoroacetic acid (1ml) and cycloheptanone (560mg) were added and the reflux continued for about 4 hours. Solvent is moved under reduced pressure • 60- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1236477 A7 ----β "!------ V. Description of the invention (58 ) Except. To the residue were added 20 ml of ethyl acetate and 10% NaHC03 solution. After pouring, the substrate was washed with water and dried on MgS04. The solvent was evaporated to provide a residue, which was purified by flash chromatography on silica gel (eluent: heptane / ethyl acetate 3: 7). The pure separated fractions were collected and concentrated to obtain 80 g of the title compound "Melting point: 208-210 ° C. Example 1502 (3R) -3- (4-phenyl-1H-imidazol-2-yl) _2,3,4,9-tetrahydro-1 丨-[3- (4methylphenyl) -1- Propionyl] spiro [IH-) S -carboline-1,4, -piperidine]

對20ml的無水四氩咬味予以加入（192mg，1 mmol)的 1-(3-二甲基胺基丙基）-3-乙基碳化二亞胺氣化氫與（〇.14ml， 1 mmol)的三乙胺。將混合物攪拌歷時大約15分鐘，接而 予以加入（3R)-3-(4-苯基-1H咪唑-2基）-2,3,4,9-四氫-螺狀 (ΙΗ-冷-咔啉-1，4，-哌啶](383mg，1 mmol)以及3-(4-甲基苯 -61 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ^ --------ti-------^ (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印剔衣 1236477 A7 __________ B7 五、發明說明（59) 基）丙酸（164mg，1 mm〇i)。將反應混合物溫熱至大約4〇 °C並在此溫度下予以攪拌過夜。溶劑於減壓下被移除。所 形成的殘餘物在乙酸乙酯（20ml)與水（10ml)之間作分部分 離。在傾倒後，有基層以10% NaHC03溶液、水予以清洗， 並於MgS〇1 2 3上乾燥。蒸發掉溶劑而提供一個殘餘物，且藉 由於矽膠上進行閃蒸層析法（洗提液：乙酸乙酯/二氣甲烷 1:1)予以純化之。收集純質的分離部分並將之濃縮。得到 之白色固體以二乙基醚予以清洗，並藉由過濾而得到100g 的標題化合物。熔點：180-182°C。 實施例1503 (3R)-3-(4-笨基-1H-咪唑-2 基）-2,3,4,9-四氫-Γ-[Ν_(4-三氟 甲基苯基）羰醯胺]螺狀[1 H-泠-咔啉-1，4、哌啶]20 ml of anhydrous tetra argon was added (192 mg, 1 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide gasified with (0.14 ml, 1 mmol) ) Triethylamine. The mixture was stirred for about 15 minutes, and then (3R) -3- (4-phenyl-1H imidazol-2yl) -2,3,4,9-tetrahydro-spiral (Ι (-冷-卡) was added. Porphyrin-1,4, -piperidine] (383mg, 1 mmol) and 3- (4-methylbenzene-61-This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) ^- ------ ti ------- ^ (Please read the notes on the back before filling out this page) The Intellectual Property Bureau of the Ministry of Economic Affairs, Employee Consumption Cooperative, India, 1236477 A7 __________ B7 V. Description of Invention (59) Propyl) propanoic acid (164 mg, 1 mmi). The reaction mixture was warmed to about 40 ° C and stirred at this temperature overnight. The solvent was removed under reduced pressure. The residue formed was in ethyl acetate Ester (20ml) and water (10ml) were separated in sections. After pouring, the substrate was washed with 10% NaHC03 solution, water, and dried over MgS02 23. The solvent was evaporated to provide a residue. And purified by flash chromatography on silica gel (eluent: ethyl acetate / digas methane 1: 1). The pure separated fractions were collected and concentrated. The obtained white solid was diethyl ether. Ether After washing, 100 g of the title compound was obtained by filtration. Melting point: 180-182 ° C. Example 1503 (3R) -3- (4-benzyl-1H-imidazol-2yl) -2,3,4 , 9-Tetrahydro-Γ- [N_ (4-trifluoromethylphenyl) carboxamide] Spiro [1 H-ling-carboline-1,4, piperidine]

對一個配於二氣甲烷内之（3尺)-3-(4-卩1^117丨-111-咪唑- (請先閱讀背面之注意事項再填寫本頁)For a (3 feet) -3- (4- 卩 1 ^ 117 丨 -111-imidazole) in digas methane (Please read the precautions on the back before filling this page)

1 基）-2,3,4,9 四氫-螺狀[1H-石-咔啉-1,4，-哌啶](383mg，1 mmol)溶液予以加入（187mg，1 mmol)的4-三氟曱基苯基異 氰酸酯。混合物被攪拌歷時大約1小時並以20ml的二乙基 2 -62· 3 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1236477 A’7 — ___— _B7__ 五、發明說明（6〇 ) 醚予以稀釋。藉由過濾來收集淺乳黃色沉澱物，並以二乙 基醚予以清洗而得到140mg的標題化合物。熔點：222-224 〇C。 f施例1504 特-丁基（lR)-2-胺基-1-(1H-吲哚-3-基甲基）-2-氧基乙基胺 基曱酸酯 NH.1 group) -2,3,4,9 tetrahydro-spiro [1H-stone-carboline-1,4, -piperidine] (383 mg, 1 mmol) solution was added (187 mg, 1 mmol) of 4- Trifluorofluorenylphenyl isocyanate. The mixture was stirred for about 1 hour and 20 ml of diethyl 2-62 · 3 was used. The paper size was in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1236477 A'7 — ___ — _B7__ 5. Description of the invention (60) The ether is diluted. The pale milky yellow precipitate was collected by filtration and washed with diethyl ether to obtain 140 mg of the title compound. Melting point: 222-224 ° C. f Example 1504 tert-butyl (lR) -2-amino-1- (1H-indol-3-ylmethyl) -2-oxyethylaminophosphonate NH.

ΟH3C—、CH3 ch3 在一個壓力為200psi的反應器内予以加入（6.2g， 22mmol)的曱基（2R)-2[(特-丁氧基羰基）胺基]-3-(1Η-吲嗦-3-基）丙酸酯以及120 ml的被飽和以ΝΗ3之甲醇。在大約85 °C下攪拌溶液歷時大約24小時。在冷卻後，將溶液蒸發， 並殘餘物藉由加入二異丙基醚而被沉澱出。經由過濾得到 5.4g的標題化合物。熔點：i42-143°C。 特-丁基（lR)-2-胺基吲哚-3-基甲基）_2_硫氧乙基胺 基曱酸醋 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) -------------裝 LSJ· i線· 1236477ΟH3C—, CH3 and ch3 were charged into a reactor with a pressure of 200 psi (6.2 g, 22 mmol) of fluorenyl (2R) -2 [(tert-butoxycarbonyl) amino] -3- (1 嗦 -indene). -3-yl) propionate and 120 ml of methanol saturated with NH3. The solution was stirred at about 85 ° C for about 24 hours. After cooling, the solution was evaporated and the residue was precipitated by adding diisopropyl ether. 5.4 g of the title compound was obtained through filtration. Melting point: i42-143 ° C. Tert-butyl (lR) -2-amino indole-3-ylmethyl) _2_thiooxyethylamino acetic acid vinegar This paper is sized for China National Standard (CNS) A4 (210 X 297 mm) ) (Please read the precautions on the back before filling this page) ------------- Install LSJ · i cable · 1236477

f請先閱讀背面之注意事項再填寫本頁) Ο H3C^pCH3 ch3 對一個配於85ml的1，2-二甲氧基乙烷内之（5g， 16〇mm〇1)的特-丁基 UR)-2-胺基㈣ _3_基甲基）-2-一 基基甲酸g旨溶液予以加入(62mmol)的 4. 經濟部智慧財產局員工消費合作社印製f Please read the notes on the back before filling in this page) 〇 H3C ^ pCH3 ch3 To a t-butyl compound (5g, 160mm) in 85ml of 1,2-dimethoxyethane UR) -2-Aminopyrene _3_ylmethyl) -2-monocarboxylic acid g solution was added (62mmol) 4. Printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs

NaHC03 ’並接而加入（73g，32nimol)的P2S5歷時一段大約 45刀鐘之期間。授拌混合物過夜，並蒸發掉溶劑。將殘餘 物散浮於乙酸乙酯内，並使用水、10% NaHC03溶液以及 水予以清洗之。於MgS〇4上乾燥過後，有基層被濃縮，而 粗產物藉由加入異戊烷/二異丙基醚1:1被沉澱之。經由過 渡得到有如一乳黃色粉末之4.3g的標題化合物。MS : 320.2 (MH+) TLC : Rf= 0.7 (CH2Cl2/MeOH 90:10)。 特-丁基（1R)_2-(1H-吲哚-3基）-1-(4-苯基-1，3-噻唑_2_基）胺 基甲酸乙St -64- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1236477NaHC03 'was added in parallel (73g, 32nimol) of P2S5 over a period of approximately 45 knife minutes. The mixture was stirred overnight and the solvent was evaporated. The residue was suspended in ethyl acetate and washed with water, 10% NaHC03 solution and water. After drying over MgSO4, a base layer was concentrated, and the crude product was precipitated by adding isopentane / diisopropyl ether 1: 1. Upon transit, 4.3 g of the title compound was obtained as a milky yellow powder. MS: 320.2 (MH +) TLC: Rf = 0.7 (CH2Cl2 / MeOH 90:10). Tert-butyl (1R) _2- (1H-indole-3yl) -1- (4-phenyl-1,3-thiazole_2_yl) aminoformic acid ethyl St -64- This paper is for China National Standard (CNS) A4 Specification (210 X 297 mm) 1236477

立、發明說明（a)Legislation, invention description (a)

(請先閱讀背面之注意事項再填寫本頁} ο H3C~j-CH3 ch3 一個（2.248，7111111〇1)的特-丁基（11^)-2-胺基-1-(111-吲 嘴-3-基甲基）-2硫氧乙基胺基甲酸酯以及（1.4g，7mm〇i)的 α -溴乙醯苯之混合物倍加熱直至完全熔化（90°c)。維持 該溫度在大約90°C歷時大約1〇分鐘，並於冷卻後予以加入 乙酸乙酯（50ml)與水（25ml)。傾倒有機層，以10% NaHC03 溶液予以清洗，於MgS04上乾燥。在溶劑蒸發之後提供一 個殘餘物，且藉由於矽膠上進行閃蒸層析法（洗提液：二 氣甲烷/乙酸乙酯95:5)予以純化之。收集純質的分離部分 並將之濃縮，而得到1 · 1 g之如同一乳黃色粉末的所欲產 遂齊茚皆这5讨轰DlrMnrr.肖費.乍i 物。MS : 420·2 (MH+) ; TLC : Rf= 0.7 (Si02; CH2Cl2/EtOAc 95:5) 〇 (lR)-2-(lH-吲哚-3-基）-1-(4-苯基-1，3-噻唑-2-基）-1-乙胺氣 化氮 -65- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1236477 A7(Please read the precautions on the back before filling out this page} ο H3C ~ j-CH3 ch3 One (2.248, 7111111〇1) t-butyl (11 ^)-2-amino-1- (111-indole) A mixture of -3-ylmethyl) -2thiooxyethylaminocarbamate and (1.4 g, 7 mm) of α-bromoacetophenone is heated until completely melted (90 ° c). Maintaining this temperature At about 90 ° C for about 10 minutes, and after cooling, ethyl acetate (50ml) and water (25ml) were added. The organic layer was poured, washed with a 10% NaHC03 solution, and dried over MgS04. After the solvent was evaporated A residue was provided and purified by flash chromatography on silica gel (eluent: methane / ethyl acetate 95: 5). The pure isolated fractions were collected and concentrated to give 1 · 1 g of the same milky yellow powder to produce the desired zircene are 5 DlrMnrr. Shao Fei. The first thing. MS: 420.2 (MH +); TLC: Rf = 0.7 (Si02; CH2Cl2 / EtOAc 95: 5) 〇 (lR) -2- (lH-indole-3-yl) -1- (4-phenyl-1,3-thiazol-2-yl) -1-ethylamine gasification nitrogen-65 -This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1236477 A7

Η 對（1.2g，2.85mmol)的特-丁基（1R)-2-(1H_吲哚-3基> 1-(4-笨基-l，3-噻唑-2-基）乙基胺基甲酸酯予以加入乙酸乙 酉曰（10ml)以及20ml的一個配於乙酸乙酯内之1N HC1溶液。 在大約20 C下授拌溶液歷時大約2小時，繼之在大約5〇。〇 下歷時大約2小時。在冷卻時所形成的晶體藉由過濾予以 收集並以二乙基醚予以清洗，而得到lg的如同一橘色粉末 之標題化合物。溶點：170-172 °C。 (3R)-1，1-二丁基-3-(4·笨基-13-噻唑·2•基）_2,3,4,9_ 四氩· 点-味琳 (請先閱讀背面之注意事項再填寫本頁) ••線· 經濟部智慧財產局員工消費合作社印製Η p- (1.2g, 2.85mmol) tert-butyl (1R) -2- (1H_indole-3yl) > 1- (4-benzyl-1,3-thiazol-2-yl) ethyl Carbamate was added with ethyl acetate (10 ml) and 20 ml of a 1N HC1 solution in ethyl acetate. The solution was incubated at about 20 C for about 2 hours, followed by about 50 ° C. It took about 2 hours. The crystals formed on cooling were collected by filtration and washed with diethyl ether to give the title compound of lg as the same orange powder. Melting point: 170-172 ° C. (3R ) -1,1-dibutyl-3- (4 · benzyl-13-thiazole · 2 • yl) _2,3,4,9_ tetraargon · dot-weilin (Please read the notes on the back before filling (This page) •• Line · Printed by the Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs

-66- 本紙張尺度適用令國國家標準（CNS)A4規格（210 X 297公釐） 1236477 五、發明說明（64) 對一個配於n-丁醇（15ml)内之（lR)-2-(lH-吲哚-3基）- 1-(4-笨基-1，3-噻唑-2基）-1-乙胺氯化氫（210mg，0.59mmol) 溶液予以加入〇.45ml (2.5mmol)的5-壬_。混合物在回留 下被加熱歷時大約兩小時，並接而藉由Dean-Stark來移除 5ml的η-丁醇。繼續回流歷時大約3小時。混合物於減壓下 被濃縮，而殘餘物在乙酸乙酯（15ml)與10% NaHC03溶液 (15ml)之間作分部分離。在傾倒後，有機層以水來清洗並 於MgS〇4上乾燥。蒸發掉溶劑而提供一個棕色的殘餘物， 且藉由於矽膠上進行閃蒸層析法（洗提液：二氣甲烷/乙酸 乙酯97:3)予以純化之《收集純質的分離部分並將之濃縮。-66- The size of this paper is applicable to the national standard (CNS) A4 specification (210 X 297 mm) 1236477 V. Description of the invention (64) For a (1R) -2- (lH-indole-3yl)-1- (4-benzyl-1,3-thiazole-2yl) -1-ethylamine hydrogen chloride (210mg, 0.59mmol) was added to a solution of 0.45ml (2.5mmol) 5- 任 _. The mixture was heated under retention for approximately two hours and then 5 ml of n-butanol was removed by Dean-Stark. Continue refluxing for approximately 3 hours. The mixture was concentrated under reduced pressure, and the residue was separated in portions between ethyl acetate (15 ml) and 10% NaHC03 solution (15 ml). After pouring, the organic layer was washed with water and dried over MgS04. The solvent was evaporated to provide a brown residue, which was purified by flash chromatography on silica gel (eluent: methane / ethyl acetate 97: 3). Of concentration.

殘餘物被溶於二乙基醚内，並加入配於乙酸乙醋内之1N HC1。此氣化氫化合物藉由過濾予以收集並以二乙基醚清 洗，而得到如同一橘色的粉末285mg的標題化合物。熔 點：134-136°C。 製品1 特-丁基（1 R)-2-(1-苯並嗔吩_3基）小(4_苯基咪唑·2基） 乙基胺基曱酸酯 . —ί-裂· I I (請先閱讀背面之注意事項再填寫本頁) 訂： -線-The residue was dissolved in diethyl ether and 1N HC1 in ethyl acetate was added. This hydrogenated hydrogen compound was collected by filtration and washed with diethyl ether to obtain 285 mg of the title compound as an orange powder. Melting point: 134-136 ° C. Product 1 tert-butyl (1 R) -2- (1-benzofluoren-3-yl) small (4-phenylimidazole · 2-yl) ethylamino phosphonate. —Ί-crack II ( (Please read the notes on the back before filling out this page) Order: -line-

1236477 A/ B7___ 五、發明說明（65 ) 對一個配於無水乙醇（60mi)與水（20ml)内之Boc-D-3-苯並σ塞吩基丙胺酸（5g，15mmol)溶液予以加入碳酸絶（2.4g， 7.5mmol)，而混合物在大約20°C下予以擾拌歷時大約2小 時。溶劑於減壓下被移除，而提供一個白色粉末，並將之 溶於二甲基甲醯胺（100ml)内，並以α -溴乙醯苯（3g， 15mmol)予以處理。在大約20°C下予以攪拌過夜後，溶劑 於減壓下被濃縮。殘餘物以乙酸乙酯（100ml)予以處理， 而由之而得的沉殿物（CsBr)被過瀘、掉，以乙酸乙g旨予以清 洗，且過濾液於減壓下被濃縮，而提供一個淡標色固鱧。 此固體被溶於二甲苯（l〇〇ml)内，予以加入醋酸按（23g， 300mmol)，而混合物予以回流歷時大約2小時。在冷卻至 大約20°C後，予以加入水（50ml)以及乙酸乙酯（i〇〇mi)。 傾倒有機層，並以水（50ml)、10% NaHC03溶液（2x50ml)、 鹽水（50ml)予以清洗，且於MgS〇4上乾燥《溶劑於減壓下 被蒸發。對殘餘物予以加入異戊烧（60ml)，接而將之過遽 而提供4g的標題化合物。溶點：116-120°C。 製品2 特-丁基（lR)-l-(4,5-二曱基-1，3-β惡唾-2 基）-2-(1 Η -弓丨嗓-3- 基）乙基胺基甲酸酯 -68- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------ - — 訂！ —----線 — · (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 12364771236477 A / B7___ V. Description of the invention (65) Carbonic acid (5g, 15mmol) was added to a solution of Boc-D-3-benzoσsedenylalanine (5g, 15mmol) in absolute ethanol (60mi) and water (20ml). (2.4 g, 7.5 mmol), and the mixture was stirred at about 20 ° C for about 2 hours. The solvent was removed under reduced pressure to provide a white powder, which was dissolved in dimethylformamide (100 ml) and treated with α-bromoacetophenone (3 g, 15 mmol). After stirring at about 20 ° C overnight, the solvent was concentrated under reduced pressure. The residue was treated with ethyl acetate (100ml), and the sanctuary (CsBr) obtained therefrom was washed and discarded, washed with ethyl acetate g, and the filtrate was concentrated under reduced pressure to provide A light-toned color is fixed. This solid was dissolved in xylene (100 ml), acetic acid (23 g, 300 mmol) was added, and the mixture was refluxed for about 2 hours. After cooling to about 20 ° C, water (50 ml) and ethyl acetate (100 mi) were added. The organic layer was decanted and washed with water (50 ml), 10% NaHC03 solution (2 x 50 ml), brine (50 ml), and dried over MgS04. The solvent was evaporated under reduced pressure. Isoprene (60 ml) was added to the residue, which was then passed through to provide 4 g of the title compound. Melting point: 116-120 ° C. Product 2 tert-butyl (lR) -l- (4,5-difluorenyl-1,3-βoxasalyl-2) -2- (1 Η-bendo-3-yl) ethylamine Carbamate-68- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) --------Order! —---- Line — · (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1236477

A7 ----------B7 五、發明說明（66 ) 0 卞 ch3 ch3 對一個配於無水乙醇（80ml)内之Bqc-D-TRP-OH (15g， 34mmol)溶液予以加入碳酸铯（5.5g，17ππη〇1)。在大約20 c下攪拌混合物歷時大約1小時，並於減壓下將之濃縮而 提供一個白色粉末，並將之溶於二甲基甲醯胺（10〇ml)内， 並以3_溴基-2-丁酮（3.56ml，34mmol)予以處理。在大約20 C下予以攪拌大約2小時後，溶劑於減壓下被移除以提供 一個散浮液，且以乙酸乙酯予以處理之。沉殿物（CsBr)被 過濾掉，而過濾液被蒸發以提供一油，並將之溶於二甲苯 (400ml)内。加入醋酸錄（52g，680mmol)，而混合物予以回 流歷時大約45分鐘。在冷卻至大約2〇〇c後，予以加入水 (150ml)以及乙酸乙酯（i〇〇mi)。在傾倒有機層後，以水 (100ml)、10% NaHC03 溶液（2xl〇〇mi)、鹽水（100ml)予以 清洗，於MgSCU上乾燥，且溶劑於減壓下被蒸發。殘餘物 藉由乙酸乙酯/庚烷1:1作為洗提液而於矽膠上進行閃蒸層 析法來予以純化，而提供3g之有如一個白色粉末的標題化 合物。熔點：138-140°C。 下面之化合物表係例示依據本發明而被合成出的一 -69- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱) ------ -------------I--------^0--------^ (請先閱讀背面之注意事項再填寫本頁) 1236477 λ： -------- B7 五、發明說明（67) 些化合物，並提估每一化合物之HPLC滯留時間（以分鐘計） 以及質譜結果。 質譜係在一個單一的四極電噴霧質譜儀（Micromass， Platform model)上，〇·8 Da解析度，而被獲得。以碘化鈉 與碘化铷溶液異丙醇/水（1/1 Vol.)來進行介於80 and 1000 D a間之每個月的校正。 HPLC滯留時間係藉由在一個配備有一個光二極管列 陣 UV偵測器的 HPLC 系統：HP1100 (HewlettPackard)上而 被獲得。 HPLC條件係如下述，且對於每一個化合物表中所用 的條件被示於加熱攔中。 條件A : 溶劑：A :水+ 0.04%三氟乙酸 B :乙腈 時間（分鐘） Α% Β% 0 100 0 1 100 0 8 30 70 10 30 70 流速：1 · 1 ml/min 注射容積：5 μί 管柱：Uptisphere ODS 3μπι 33 * 4·6 mm i.d. 溫度：：40 °C 波長：220 nm 條件A被應用於具有式2、3與4的化合物之表的化合 物之HPLC分析。 條件B : -70· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) ---I II I 訂-----!· *5^ 丨· 經濟部智慧財產局員工消費合作社印製 -ϋ ϋ ϋ I ϋ I n n n ϋ ϋ n ϋ - A7 B7 1236477A7 ---------- B7 V. Description of the invention (66) 0 卞 ch3 ch3 Add a solution of Bqc-D-TRP-OH (15g, 34mmol) in absolute ethanol (80ml) to carbonic acid Cesium (5.5g, 17ππη〇1). The mixture was stirred at about 20 c for about 1 hour, and concentrated under reduced pressure to provide a white powder, which was dissolved in dimethylformamide (100 ml) and treated with 3-bromo 2-Butanone (3.56 ml, 34 mmol) was treated. After being stirred at about 20 C for about 2 hours, the solvent was removed under reduced pressure to provide a floating liquid, and it was treated with ethyl acetate. The sinker (CsBr) was filtered off, and the filtrate was evaporated to provide an oil, which was dissolved in xylene (400 ml). Acetic acid (52 g, 680 mmol) was added, and the mixture was refluxed for approximately 45 minutes. After cooling to about 200c, water (150ml) and ethyl acetate (100mi) were added. After the organic layer was poured, it was washed with water (100 ml), 10% NaHC03 solution (2 × 100 mi), brine (100 ml), dried over MgSCU, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate / heptane 1: 1 as the eluent to provide 3 g of the title compound as a white powder. Melting point: 138-140 ° C. The following compound table is an example of the one-69-synthesized according to the present invention. This paper size is applicable to China National Standard (CNS) A4 (210 X 297 public love). ------ ------- ------ I -------- ^ 0 -------- ^ (Please read the notes on the back before filling this page) 1236477 λ: -------- B7 V. Description of the invention (67) These compounds, and estimate the HPLC retention time (in minutes) and mass spectrometry results of each compound. Mass spectra were obtained on a single quadrupole electrospray mass spectrometer (Micromass, Platform model) with a resolution of 0.8 Da. Sodium iodide and thallium iodide solution isopropanol / water (1/1 Vol.) Was used to perform monthly calibrations between 80 and 1000 D a. HPLC residence time was obtained on an HPLC system equipped with a photodiode array UV detector: HP1100 (HewlettPackard). The HPLC conditions are as follows, and the conditions used in each compound table are shown in a heating block. Condition A: Solvent: A: Water + 0.04% trifluoroacetic acid B: Acetonitrile Time (minutes) Α% Β% 0 100 0 1 100 0 8 30 70 10 30 70 Flow rate: 1 · 1 ml / min Injection volume: 5 μί Column: Uptisphere ODS 3 μm 33 * 4.6 mm id Temperature: 40 ° C Wavelength: 220 nm Condition A was applied to HPLC analysis of compounds having the tables of compounds of Formulas 2, 3 and 4. Condition B: -70 · This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) --- I II I Order ----- * 5 * 丨 · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs-ϋ ϋ ϋ I ϋ I nnn ϋ ϋ n ϋ-A7 B7 1236477

五、發明說明（0S 溶劑V. Description of the invention (0S solvent

A B 水+ 0·04%三氟乙酸 乙腈 畚間（分鐘） A% B% 一^ 0 100 0 1 100 0 8 30 70 10 30 70 (請先閱讀背面之注意事項再填寫本頁) 流速：1.1 ml/min 注射容積：5 μί 管柱：Uptisphere ODS 3μιη 33 氺 4·6 mm i.d· 溫度：：40 °C 波長：220 nm 條件B被應用於具有式1的化合物之表的化合物之 HPLC分析。 條件C : 溶劑：A :水+ 〇·〇4%三氟乙酸 B :乙腈 時間（分鐘） A% B% 0 90 0 1 90 0 8 30 100 10 30 100AB water + 0 · 04% trifluoroacetic acid acetonitrile (minutes) A% B% 1 ^ 0 100 0 1 100 0 8 30 70 10 30 70 (Please read the precautions on the back before filling this page) Flow rate: 1.1 ml / min Injection volume: 5 μί Column: Uptisphere ODS 3 μm 33 4.6 mm id · Temperature: 40 ° C Wavelength: 220 nm Condition B was applied to the HPLC analysis of compounds having the table of compounds of formula 1. Condition C: Solvent: A: Water + 〇.04% trifluoroacetic acid B: Acetonitrile Time (minutes) A% B% 0 90 0 1 90 0 8 30 100 10 30 100

流速：1 · 1 ml/min 注射容積：5 pL 管柱：Uptisphere ODS 3μιη 33 * 4.6 mm i.d. 溫度：：40 °C 波長：220 nm 條件C被應用於具有式5的化合物之表的化合物之 HPLC分析 L· -71 · 本紙張尺度適用中國國家標準（CNS)A4規格（210x 297公釐） 1236477 A7 B7 五、發明說明u?) 經濟部智慧財產局員工消費合作社印製 VNH Λη ― οτ- 化學式1 Η 分析 R2 R3 Rt (min) (M+H)+ 1 會 4.6 493.3 2 αχτ' 會 5.1 553.3 3 >ΝΗ · * 4.9 506.4 4 •、力 會 5.0 471.3 5 • r 會 4.7 493.4 6 會 4.7 471.3 7 hn-s^Qtoh 畲 5.8 500.3 8 ^r〇 • ,HN /N-/ v # 7.2 574.3 9 * 、 * 4.7 477.4 10 /N/ v 4.4 520.4 (請先閱讀背面之注意事項再填寫本頁) n n n n^-OJB I n n n ϋ I 1 I ϋ ·ϋ ·ϋ .^1 l 1« n n ·_ϋ «1-— ϋ n ϋ ϋ ϋ ϋ n ·ϋ ·ϋ H ^1 1 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -72- 痤齊ΪΡ皆瘘讨轰苟員11将費^乍：緹 1236477 A7 37 η 五、發明說明 nvnh rSn Η 化學式1 分析 R2 R3 Rt (min) (M+H)+ 10 • 广V， * 4.4 520.4 11 、 ην，^ν’一ρ O’ 4.8 519.3 12 OLCr'. 0’ 5.3 579.4 13 ,·.νη 0’ 5.1 532.4 14 * 。’ 5.2 497.3 15 . r 。’ 4.9 519.4 16 〇^νη、· N^/ 。’ 4.9 497.3 17 • HN^x^Or〇H 。’ 6.0 526.3 18 °yO • #HN 。’ 7.4 600.4 ---------------裝---(請先閱讀背面之注意事項再填寫本頁) •線· I紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -73 - 1236477 A7 B7 五、發明說明0/) 經濟部智慧財產局員工消費合作社印製 七 n^-nh or- 化學式1 H 分析 R2 R3 Rt (min) (M+H)+ 19 4.9 503.4 20 • rf 0’ 4.6 546.4 21 會 V ^ HN〜N0〇 x〇 5.0 ； 4.9 588.3 22 〇L〇r'. 5.4 ; 5.3 648.3 23 N-N V NH 声 ♦ /〇 5.2 ; 5.1 601.3 24 P^no2 /〇 5.4 ; 5.3 566.2 25 * r · v ..¾. x〇 5.05 ; 4.97 588.3 26 N^/ Q:。: /0 5.1 ; 5.0 566.2 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -74- 1236477 Α7 Β7 明說明（K) 發 五 經齊部智慧时轰笱員X.消費合昨眛印製 VNH f^NH · or- Η 化學式1 分析 R2 R3 Rt (min) (M+H 卜 27 # 、ΗΝ^〇^ΟΗ ft. /〇 6.2:6.1 595.3 28 °y〇 .-HN /0 7.4 669.3 29 # hn-^nQ /0 5.05 ; 4.95 572.3 30 • rf ft〇2 4.7 615.3 31 # 、 /---- HN 〜N0〇 * 5.0 557.3 32 our'. 會 5.4 617.4 33 /^* N-N /NH 會 會 5.2 570.3 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁)Flow rate: 1 · 1 ml / min Injection volume: 5 pL Column: Uptisphere ODS 3μιη 33 * 4.6 mm id Temperature: 40 ° C Wavelength: 220 nm Condition C is applied to HPLC of compounds having the table of compounds of formula 5 Analysis L · -71 · This paper size is in accordance with Chinese National Standard (CNS) A4 (210x 297 mm) 1236477 A7 B7 V. Description of the invention u?) VNH printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Λη ― οτ- chemical formula 1 Η Analysis R2 R3 Rt (min) (M + H) + 1 will be 4.6 493.3 2 αχτ 'will be 5.1 553.3 3 > NΗ · * 4.9 506.4 4 •, force will be 5.0 471.3 5 • r will be 4.7 493.4 6 will be 4.7 471.3 7 hn-s ^ Qtoh 畲 5.8 500.3 8 ^ r〇 •, HN / N- / v # 7.2 574.3 9 *, * 4.7 477.4 10 / N / v 4.4 520.4 (Please read the precautions on the back before filling this page) nnnn ^ -OJB I nnn ϋ I 1 I ϋ · ϋ · ϋ. ^ 1 l 1 «nn · _ϋ« 1-— ϋ n ϋ ϋ ϋ ϋ n · ϋ · ϋ H ^ 1 1 This paper size applies to Chinese national standards (CNS) A4 specifications (210 X 297 mm) -72- Acne qi is a fistula to discuss the members 11 will charge ^ First: Ti 1236477 A7 37 η Description nvnh rSn Η Chemical formula 1 Analysis R2 R3 Rt (min) (M + H) + 10 • Wide V, * 4.4 520.4 11, ην, ^ ν'-ρ O '4.8 519.3 12 OLCr'. 0 '5.3 579.4 13, · .Νη 0 '5.1 532.4 14 *. ’5.2 497.3 15. R. ’4.9 519.4 16 〇 ^ νη, · N ^ /. ’4.9 497.3 17 • HN ^ x ^ Or〇H. ’6.0 526.3 18 ° yO • #HN. '7.4 600.4 --------------- Packing --- (Please read the precautions on the back before filling out this page) • Line · I paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) -73-1236477 A7 B7 V. Description of the invention 0 /) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs n ^ -nh or- Chemical formula 1 H Analysis R2 R3 Rt (min) (M + H) + 19 4.9 503.4 20 • rf 0 '4.6 546.4 21 will be V ^ HN ~ N0〇x〇5.0; 4.9 588.3 22 〇L〇r'. 5.4; 5.3 648.3 23 NN V NH sound ♦ /〇5.2; 5.1 601.3 24 P ^ no2 / 〇5.4; 5.3 566.2 25 * r · v .. ¾. X〇5.05; 4.97 588.3 26 N ^ / Q :. : / 0 5.1; 5.0 566.2 (Please read the notes on the back before filling out this page) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -74- 1236477 Α7 Β7 Instructions (K) When the wisdom of the Five Classics was published, the member X. Consumers printed VNH f ^ NH · or- yesterday. Chemical formula 1 analysis R2 R3 Rt (min) (M + H 卜 27 # 、 ΗΝ ^ 〇 ^ 〇 ^ ft. / 〇6.2: 6.1 595.3 28 ° y〇.-HN / 0 7.4 669.3 29 # hn- ^ nQ / 0 5.05; 4.95 572.3 30 • rf ft〇2 4.7 615.3 31 #, / ---- HN ~ N0〇 * 5.0 557.3 32 our '. Meeting 5.4 617.4 33 / ^ * NN / NH Meeting 5.2 570.3 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling out this page )

-75· 1236477 A7 B7 五、發明說明（；?3) 經濟部智慧財產局員工消費合作社印製 七 n^-nh ατ- Η 化學式1 分析 R2 R3 Rt (min) (M+H)+ 34 O^〇v/-v 禽 5.4 535.3 35 * ^ O^oy、 會 5.1 557.4 36 CV&quot;NH … • 5.1 535.3 37 會 6.2 564.3 38 〆HN Ov^〇，' 7.5 638.4 39 會 hn〜0 會 5.1 541.3 40 . rf # 4.8 584.4 41 * HN〜N0〇 οσ* 4.7 557.3 42 OXr'. &lt;:xy· 5.1 617.3 (請先閲讀背面之注意事項再填寫本頁) -ei .LHMI * -裝—--訂-----ί· •線丨·1 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐) -76 - 1236477 A7B7 j五經齊郎智慧时轰咼員X消費合泎；ϋ印製 發明說明（夕义) nvnh or- Η 化學式1 分析 R2 R3 Rt (min) (M+H)+ 43 —'、 r— Ν-Ν V • /ΝΗ &lt;:xx * 4.9 570.3 44 •，ην力 5.0 535.3 45 * r &lt;:〇’ 4.8 557.3 46 〇wnh、曹 N^/ OD·’ 4.8 535.2 47 * hn^〇^oh &lt;XT· 5.8 564.3 48 °yO 〆HN 7.2 638.3 49 * hn〜0 〇〇’ 4.7 541.3 • 50 〈XT· 6.3 570.2 51 * 、 r0^ hn〜n〇〇 、siT. 5.0 559.3 •-------------裝---(請先閱讀背面之注意事項再填寫本頁) L§J· :線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -77- 1236477 a7 B7-75 · 1236477 A7 B7 V. Description of the invention (; 3) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs n ^ -nh ατ- Η Chemical formula 1 Analysis R2 R3 Rt (min) (M + H) + 34 O ^ 〇v / -v poultry 5.4 535.3 35 * ^ O ^ oy, will be 5.1 557.4 36 CV &quot; NH… • 5.1 535.3 37 will be 6.2 564.3 38 〆HN Ov ^ 〇, '7.5 638.4 39 will be hn ~ 0 will be 5.1 541.3 40 . rf # 4.8 584.4 41 * HN ~ N0〇οσ * 4.7 557.3 42 OXr '. &lt;: xy · 5.1 617.3 (Please read the precautions on the back before filling out this page) -ei .LHMI * -installation --- order ----- ί · • Line 丨 · 1 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) -76-1236477 A7B7 j Wu Jing Qi Lang Wisdom Time Member X Consumption; ϋPrinted invention description (Xiyi) nvnh or- Η Chemical formula 1 Analysis R2 R3 Rt (min) (M + H) + 43 — ', r— Ν-Ν V • / ΝΗ &lt;: xx * 4.9 570.3 44 • , Ην force 5.0 535.3 45 * r &lt;: 〇 '4.8 557.3 46 〇wnh, Cao N ^ / OD ·' 4.8 535.2 47 * hn ^ 〇 ^ oh &lt; XT · 5.8 564.3 48 ° yO 〆HN 7.2 638.3 49 * hn ~ 0 〇〇 '4.7 541.3 • 50 <XT · 6.3 570.2 51 *, r0 ^ hn ~ n〇〇, siT. 5.0 559.3 • ------------- install --- (Please read the precautions on the back before filling in this (Page) L§J ·: Line · This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -77- 1236477 a7 B7

五、發明說明（々D / 經濟部智慧財產局員工消費合作社印製 VNH ατ- Η 化學式1 分析 R2 R3 Rt (min) (M+H)+ 52 our'. 、so’ 5.4 619.3 53 N-N V &gt;· 會 、SD’ 5.2 572.3 54 . '、力 、sj〇，’ 5.4 537.3 55 • r 、sxr· 5.1 559.3 56 、sj〇，· 5.1 537.3 57 HN^O^0H 、siT· 6.1 566.3 58 °yO 〆__ 7.5 640.3 59 會 Ο 、sxr. 5.0 543.3 (請先閱讀背面之注意事項再填寫本頁)V. Description of the invention (々D / Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy VNH ατ- Η Chemical formula 1 Analysis R2 R3 Rt (min) (M + H) + 52 our '., So' 5.4 619.3 53 NN V &gt; · Meeting, SD '5.2 572.3 54.', Force, sj〇, '5.4 537.3 55 • r, sxr5.1 559.3 56, sj〇, 5.1 537.3 57 HN ^ O ^ 0H, siT 6.1 566.3 58 ° yO 〆__ 7.5 640.3 59 Meeting 〇 sxr. 5.0 543.3 (Please read the precautions on the back before filling this page)

ί線. 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） -78- 明 發 五 痤齊郎智慧时¾¾員I.消費合阼；ϋ印製 1236477 A7 B7 說明 七 Vnh ccf- Η 化學式1 分析 R2 R3 Rt (min) (M+H)+ 60 會 A F , 力 、so’ 6.6 572.2 61 ' /、 HN 〜N0〇 、s〜 T 會 4.5 511.3 62 、S〜 T 會 5.0 571.3 63 一Vn 广' V 眷 、S〜 T 翁 4.7 524.3 64 、S〜 ? 4.9 489.3 65 • Γ&quot; 、s〜 ▼ * 4.6 511.3 66 〇^ΝΗ ‘· N^/ 、s〜 T 會 4.6 489.3 67 # 'hn'O^oh 、s〜 T 〜 會 5.7 518.3 --------------裝--- (請先閱讀背面之注意事項再填寫本頁) -i-d. --線' 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -79- 1236477 ^ A/ B7 五、發明說明) 經濟部智慧財產局員工消费合作社印製 NVNH p'NH or- Η 化學式1 分析 R2 R3 Rt (min) (M+H)+ 68 yHN 、S〜 T * 7.1 592.3 69 、S〜 T • 4.6 495.3 70 、S〜 T # 6.2 524.3 71 、 ην〜ν〇〇 、Nv0O’ I 4.1 614.4 72 our'· xy · I 4.5 674.4 73 Ν-Ν V /ΝΗ 會 〇，· I 4.3 627.4 74 XX* —I 4.4 592.3 75 • r I 4.2 614.4 (請先閱讀背面之注意事項再填寫本頁) 訂·· --線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -80- A7 1236477 ___B7 五、發明說明（# ) 0ί Line. This paper size applies Chinese National Standard (CNS) A4 specification (210 χ 297 mm) -78- Mingfa Wuac Qilang Wisdom ¾¾ members I. Consumption; printed 1236477 A7 B7 Description Seven Vnh ccf- Η Chemical formula 1 Analysis R2 R3 Rt (min) (M + H) + 60 will be AF, force, so '6.6 572.2 61' /, HN ~ N0〇, s ~ T will be 4.5 511.3 62, S ~ T will be 5.0 571.3 63 One Vn Guang 'V dependent, S ~ T Weng 4.7 524.3 64, S ~? 4.9 489.3 65 • Γ &quot;, s ~ ▼ * 4.6 511.3 66 〇 ^ ΝΗ' · N ^ /, s ~ T will 4.6 489.3 67 # 'hn'O ^ oh, s ~ T ~ will 5.7 518.3 -------------- install --- (Please read the precautions on the back before filling this page) -id.- -Line 'This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) -79- 1236477 ^ A / B7 V. Description of Invention) Printed by NVHC p'NH or -Η Chemical formula 1 analysis R2 R3 Rt (min) (M + H) + 68 yHN, S ~ T * 7.1 592.3 69, S ~ T • 4.6 495.3 70, S ~ T # 6.2 524.3 71, ην ~ ν〇〇, Nv0O 'I 4.1 614.4 72 our '· xy · I 4.5 674.4 73 Ν-Ν V / ΝΗ Meeting 〇, · I 4.3 627.4 74 XX * —I 4.4 592.3 75 • r I 4.2 614.4 (Please read the notes on the back before filling this page) Order ·· -Line · This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -80- A7 1236477 ___B7 V. Description of the invention (#) 0

Η 化學式1 分析 R2 R3 Rt(min) (M+H)+ 76 0^NH- * 0’ 1 4.2 592.3 77 會 ΗΝ、^〇τΟΗ XX* ! * 4.9 621.4 78 ^.ΗΝ XX’ I 6.1 695.4 79 〇， 1 4.2 598.4 80 ρό # 1 5.3 627.3 ' I -------------裝--- (請先閱讀背面之注意事項再填寫本頁) --線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -81 - 1236477 A7 B7 i五、發明說明（夕▼) 經濟部智慧財產局員工消費合作社印製 0 DO Onh rrUH R3 化學式2 分析 R2 R3 Rt (min) (M+HK 1 4.8 488.4 2 4.6 474.4 3 Cu、/ 5.2 552.4 4 PC, 5.2; 5.1 583.3 5 /〜CN or 4.8 552.3 6 π 5.7 564.4 7 /〜CN 4.9 538.4 8 (X 4.9 538.4 9 5.3 586.2 10 cr 5.0 514.4 11 /〜Cn 、s、/ 4.7 506.4 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -82- 1236477 A7 ____B7 五、發明說明（#) VNH 〇τ^ΝΗ R3 Η 化學式2 分析 R2 R3 Rt (min) (M+HH 12 /〜CN 。/X 5.1 553.3 13 、sxr 5.2 554.3 14 、njt I 4.5 551.4 15 pr 5.0 522.4 16 /〜CN 5.1 502.4 17 4.9 485.4 18 4.6 471.4 19 Cl^〇、/ 5.3 549.4 20 5.3 ; 5.2 580.3 21 &lt;：3T 4.9 549.3 22 5.8 561.4 • --------------裝---(請先閱讀背面之注意事項再填寫本頁) 、r· •線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -83- 1236477 A7 37 五、發明說明GP7 ) 經濟部智慧財產局員工消費合作社印製 X1 /R2 VNH . R3 Η FORMULA 2 Analysis R2 R3 Rt (min) (M+H)+ 23 4.9 535.4 24 (X I 4.9 535.4 25 Br 5.3 583.2 26 cr 5.1 511.4 27 4.8 503.4 28 5.1 550.3 29 、siT 5.2 551.3 30 I 4.6 548.4 31 9T 5.1 519.4 32 5.1 499.4 ---III — 丨 III · I I(請先閱讀背面之注意事項再填寫本頁) •線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -84- 371236477 A7 五、發明說明（P&gt;) 經濟部智慧財產局員工消費合作社印製 A /R2 rriiNH R3 H FORMULA 2 Analysis R2 R3 Rt (min) (M+H)+ 33 4.8 507.4 34 4.6 493.4 35 (X〇^ 5.2 571.4 36 /0 5.2:5.1 602.4 37 or 4.9 571.4 38 5.7 583.4 39 4.9 557.4 40 〇c 4.9 557.4 41 Br 5.3 605.3 42 cr 5.0 533,4 43 、s〜/ 4.7 525.4 (請先閱讀背面之注意事項再填寫本頁) 裝 訂· -線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ^85- 1236477 A7 B7 五、發明說明 經濟部智慧財產局員工消費合作社印製 0 on VNH α^ΝΗ R3 Η 化學式2 分析 R2 R3 Rt (min) (M+H)+ 44 。/X 5.1 572.4 45 、sxx 5.2 573.4 46 、Νχχ I 4.6 570.4 47 9T 5.0 541.4 48 5.1 521.4 49 π 4.8 471.4 50 4.6 457.4 51 (X〇、/ 5.2 535.4 52 π 0C2 /0 5.2; 5.1 566.3 53 &lt;：XX 4.8 535.3 54 5.7 547.4 裝--- (請先閱讀背面之注意事項再填寫本頁) 線 釐公 97 2 X 10 一 2 /—'格規 Α4 S) Ν (C 準標 家 國 國 中 用適 度尺張紙本 -8ό - 1236477 A7B7 五、發明說明（作) ,R2 VNH Cr^NH R3 Η 化學式2 分析 R2 R3 Rt (min) (M+H&gt;+ 55 &quot;Xl 4.9 521.3 56 〇c 4.9 521.4 57 Br 5.2 569.2 58 -Xi cr 5.0 497.4 59 、s^\/ 4.7 489.3 60 5.1 536.3 61 、sxr 5.2 537.3 62 、Nxr I 4.6 534.4 63 -Xl 9T 5.0 505.4 64 5.1 485.4 65 4.9 479.5 -1 ----------I —裝·--(請先閱讀背面之注意事項再填寫本頁) 訂·· 線 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -87- A7 經濟部智慧財產局員工消費合作社印製 1236477 _B7 五、發明說明（Ο 0 〇2 〇cVH R3 Η 化學式2 分析 R2 R3 Rt (min) (M+H)+ 66 k 八/ 4.7 465.4 67 k (X〇、/ 5.3 543.4 68 k PC〇J /〇 5.2 ; 5.3 574.4 69 k &lt;:xr 4.9 543.4 70 5.8 555.5 71 k pr x〇 5.0 529.5 72 k 〇： 5.0 529.4 73 k pr Br 5.3 577.3 74 k cr 5.1 505.5 75 k 4.8 497.4 76 k o2h^ 5.2 544.4 (請先閱讀背面之注意事項再填寫本頁) &quot;a· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -88- A7 經濟部智慧財產局員工消費合作社印製 1236477 ___B7 i / I五、發明說明（#) 1 /R2 VNH R3 Η 化學式2 分析 R2 R3 Rt (min) (M+H)+ 77 k 、sxr 5.3 . 545.4 78 、产（χ I 1 4.7 542.5 79 k 9T 5.1 513.5 80 5.2 493.5 (請先閱讀背面之注意事項再填寫本頁) ιδ· 線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐) -89- 1236477 幻 B7 經濟部智慧財產局員工消費合作社印製 R1 nA jf^l N η 化學式3 Η R2 分析 R1 R2 Rt (min) [M+H]+ 1 NO, 方 6.7 470.1 2 /0 6.4 436.1 3 CN 6.2 416.1 4 cT 〇、 6.4 451.2 5 !δ 6.3 435.1 6 !!〇 % 6.4 451.2 7 !!〇 6.3 409.1 8 !5〇 6.4 464.2 9 jac 5,5 ; 5,3 462.2 10 (^0 6.9 460.2 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -90 ~ 1236477 五、發明說明 A7 經濟邨智慧財產局員工消費合泎社印製 R1 CgiX^ 化學式3 H R2 分析 R1 R2 Rt (min) (M+HJ+ 11 !?0 / 7.4; 7,2 518.3 12 !?0 〇0 6.4 405.2 13 ^j〇 6,7 : 6.6 419.2 14 〆0 6.5 ; 6.4 395.2 15 6.6 385.2 16 6.9 399.2 17 6.2 369.2 18 !5〇 6.5 ; 6.4 385.2 19 (力 &gt;rs's&quot; 6.9 435.1 20 X0：&gt; 6.9 477.2 21 (力 n〇2 6.7 470.1 22 (^0 n〇2 6.3 436.1 ---------------裝---(請先閱讀背面之注意事項再填寫本頁) &gt;0· •線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -91 - 1236477 A7 37 c&lt;r /i\ 明說 明發五 經濟部智慧財產局員工消費合作社印製 R1 H r2 化學式3 分析 R1 R2 Rt (min) [M+H]-»· 23 (RX) CN 力 6.2 416.2 24 (RjO o&quot; 6.4 451.2 25 (r；o /-〇 6.2 435.2 26 (R；C I f 。亡 6.4 451.2 27 (R^0 6.3 409.2 28 &lt;R^0 6.4 464.2 29 (R^0 XrC 5,5; 5,3 462.2 30 (RX) 6.9 460.2 31 (^J〇 / 〇r… 7.4; 7,2 518.3 32 (R^0 〇0 6.4 405.2 33 (R^0 ^j〇 6,7; 6.6 419.2 (請先閱讀背面之注意事項再填寫本頁)分析 Chemical formula 1 analysis R2 R3 Rt (min) (M + H) + 76 0 ^ NH- * 0 '1 4.2 592.3 77 Η Ν, ^ 〇τΟΗ XX *! * 4.9 621.4 78 ^. Η XX' I 6.1 695.4 79 〇, 1 4.2 598.4 80 ρό # 1 5.3 627.3 'I ------------- install --- (please read the precautions on the back before filling this page) --- line-this paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -81-1236477 A7 B7 i V. Description of invention (Xi ▼) Printed by the Intellectual Property Bureau Staff Consumer Cooperative of the Ministry of Economic Affairs 0 DO Onh rrUH R3 Chemical Formula 2 Analysis R2 R3 Rt (min) (M + HK 1 4.8 488.4 2 4.6 474.4 3 Cu, / 5.2 552.4 4 PC, 5.2; 5.1 583.3 5 / ~ CN or 4.8 552.3 6 π 5.7 564.4 7 / ~ CN 4.9 538.4 8 (X 4.9 538.4 9 5.3 586.2 10 cr 5.0 514.4 11 / ~ Cn, s, / 4.7 506.4 (Please read the notes on the back before filling out this page) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)- 82- 1236477 A7 ____B7 V. Description of the invention (#) VNH 〇τ ^ ΝΗ R3 Η Chemical formula 2 Analysis R2 R3 Rt (min) (M + HH 12 / ~ CN. / X 5.1 553. 3 13 sxr 5.2 554.3 14 、 njt I 4.5 551.4 15 pr 5.0 522.4 16 / ~ CN 5.1 502.4 17 4.9 485.4 18 4.6 471.4 19 Cl ^ 〇, / 5.3 549.4 20 5.3; 5.2 580.3 21 &lt;: 3T 4.9 549.3 22 5.8 561.4 • -------------- install --- (please read the precautions on the back before filling this page), r · • line-This paper size applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) -83- 1236477 A7 37 V. Description of the invention GP7) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy X1 / R2 VNH. R3 Η FORMULA 2 Analysis R2 R3 Rt (min) (M + H ) + 23 4.9 535.4 24 (XI 4.9 535.4 25 Br 5.3 583.2 26 cr 5.1 511.4 27 4.8 503.4 28 5.1 550.3 29, siT 5.2 551.3 30 I 4.6 548.4 31 9T 5.1 519.4 32 5.1 499.4 --- III — 丨 III · II ( Please read the notes on the back before filling in this page) • Thread-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) -84- 371236477 A7 V. Description of Invention (P &gt;) Ministry of Economy Wisdom Printed by the property bureau employee consumer cooperative A / R2 rriiNH R3 H FORMULA 2 Analysis R2 R3 Rt (min) (M + H) + 33 4.8 507.4 34 4.6 493.4 35 (X〇 ^ 5.2 571.4 36/0 5.2: 5.1 602.4 37 or 4.9 571.4 38 5.7 583.4 39 4.9 557.4 40 〇c 4.9 557.4 41 Br 5.3 605.3 42 cr 5.0 533, 4 43 s ~ / 4.7 525.4 (Please read the precautions on the back before filling out this page) Binding ·-Thread-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 male) %) ^ 85-1236477 A7 B7 V. Description of the invention Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 0 on VNH α ^ ΝΗ R3 Η Chemical formula 2 Analysis R2 R3 Rt (min) (M + H) + 44. / X 5.1 572.4 45, sxx 5.2 573.4 46, Νχχ I 4.6 570.4 47 9T 5.0 541.4 48 5.1 521.4 49 π 4.8 471.4 50 4.6 457.4 51 (X〇, / 5.2 535.4 52 π 0C2 / 0 5.2; 5.1 566.3 53 &lt;: XX 4.8 535.3 54 5.7 547.4 Packing --- (Please read the precautions on the back before filling this page) Line centimeter 97 2 X 10 a 2 /-'standard Α4 S) Ν (C Appropriate standard for the country and the country Rule paper on paper-8ό-1236477 A7B7 V. Description of the invention (work), R2 VNH Cr ^ NH R3 Η Chemical formula 2 Analysis R2 R3 Rt (min) (M + H &gt; + 55 &quot; Xl 4.9 521.3 56 〇c 4.9 521.4 57 Br 5.2 569.2 58 -Xi cr 5.0 497.4 59, s ^ \ / 4.7 489.3 60 5.1 536.3 61, sxr 5.2 537.3 62, Nxr I 4.6 534.4 63 -Xl 9T 5.0 505.4 64 5.1 485.4 65 4.9 479.5 -1 ---- ------ I —Packing ·-(Please read the precautions on the back before filling this page) Ordering ·· The size of thread paper is applicable to China National Standard (CNS) A4 (210 X 297 mm) -87 -A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1236477 _B7 V. Description of the invention (〇 0 〇 2 〇cVH R3) Equation 2 Analysis R2 R3 Rt (min) (M + H) + 66 k eight / 4.7 465.4 67 k (X〇, / 5.3 543.4 68 k PC〇J /〇5.2; 5.3 574.4 69 k &lt;: xr 4.9 543.4 70 5.8 555.5 71 k pr x〇5.0 529.5 72 k 〇: 5.0 529.4 73 k pr Br 5.3 577.3 74 k cr 5.1 505.5 75 k 4.8 497.4 76 k o2h ^ 5.2 544.4 (Please read the notes on the back before filling this page) &quot; a · This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -88- A7 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 1236477 ___B7 i / I 5. Invention Description (#) 1 / R2 VNH R3 Η Chemical formula 2 Analysis R2 R3 Rt (min) (M + H) + 77 k, sxr 5.3. 545.4 78, production (χ I 1 4.7 542.5 79 k 9T 5.1 513.5 80 5.2 493.5 (Please read the back Note: Please fill in this page again) ιδ · Line · This paper size applies to Chinese National Standard (CNS) A4 (210 χ 297 mm) -89- 1236477 Magic B7 Printed by R1 nA jf ^ l N η Chemical formula 3 Η R2 analysis R1 R2 Rt (min) [M + H] + 1 NO, square 6.7 470.1 2/0 6.4 436.1 3 CN 6.2 416.1 4 cT 〇, 6.4 451.2 5! Δ 6.3 435.1 6 !! 〇% 6.4 451.2 7 !! 〇6.3 409.1 8! 5 06.4 464.2 9 jac 5,5; 5,3 462.2 10 (^ 0 6.9 460.2 (Please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) -90 ~ 1236477 V. Description of the invention A7 Economic Village Intellectual Property Bureau staff consumption R1 CgiX ^ Chemical formula 3 H R2 Analysis R1 R2 Rt (min) (M + HJ + 11!? 0 / 7.4; 7,2 518.3 12!? 0 〇0 6.4 405.2 13 ^ j〇6,7: 6.6 419.2 14 〆0 6.5; 6.4 395.2 15 6.6 385.2 16 6.9 399.2 17 6.2 369.2 18! 5〇6.5; 6.4 385.2 19 (Force &gt; rs's &quot; 6.9 435.1 20 X0: &gt; 6.9 477.2 21 (Force 〇2 6.7 470.1 22 ( ^ 0 n〇2 6.3 436.1 --------------- install --- (Please read the precautions on the back before filling this page) &gt; 0 · • Line-This paper size is applicable China National Standard (CNS) A4 (210 X 297 mm) -91-1236477 A7 37 c &lt; r / i Equation 3 analysis R1 R2 Rt (min) [M + H]-»23 (RX) CN force 6.2 416.2 24 (RjO o &quot; 6.4 451.2 25 (r; o / -〇 6.2 435.2 26 (R; C I f). Death 6.4 451.2 27 (R ^ 0 6.3 409.2 28 &lt; R ^ 0 6.4 464.2 29 (R ^ 0 XrC 5,5; 5,3 462.2 30 (RX) 6.9 460.2 31 (^ J〇 / 〇r ... 7.4; 7 , 2 518.3 32 (R ^ 0 〇0 6.4 405.2 33 (R ^ 0 ^ j〇6,7; 6.6 419.2 (Please read the notes on the back before filling this page))

^«,t^^(CNS)A4^(2^ ^ 1236477 :4 ：Λί Β7 ί五、發明說明（9e) ：ί -y \ 經濟部智慧財產局員工消費合作社印製 R1 H R2 化學式3 2 分析 R1 R2 Rt (min) [M+H 卜 34 (RjO 〆0 6,5 ; 6.4 395.2 35 (R；0 6.6 385.2 36 (^0 6.9 399.2 37 (R^0 6.2 369.2 38 (R；0 -&lt;I 6,5 ; 6,4 385.2 39 (RX5 ;&gt;rs、s〆 6.9 435.1 40 (RjO Λίχ) 6.9 477.2 41 N〇2 方 6.6 450.1 42 (S火 no2 力 6.3 416.2 43 (s火 CN 力 6,1 :6,0 396.2 44 (s火 0&quot; νφ 〇v 6.1 431.2 45 (s火 5¾ 6.1 415.2 (請先閱讀背面之注意事項再填寫本頁)^ «, T ^^ (CNS) A4 ^ (2 ^ ^ 1236477: 4: Λί Β7 ί V. Description of Invention (9e): ί -y \ Printed by R1 H R2 Chemical Formula 3 2 of the Consumer Cooperatives of Intellectual Property Bureau of the Ministry of Economic Affairs Analysis R1 R2 Rt (min) [M + H BU 34 (RjO 〆0 6,5; 6.4 395.2 35 (R; 0 6.6 385.2 36 (^ 0 6.9 399.2 37 (R ^ 0 6.2 369.2 38 (R; 0-&lt; I 6,5; 6,4 385.2 39 (RX5;> rs, s〆6.9 435.1 40 (RjO Λίχ) 6.9 477.2 41 N〇2 square 6.6 450.1 42 (S fire no2 force 6.3 416.2 43 (s fire CN force 6,1: 6,0 396.2 44 (s fire 0 &quot; νφ 〇v 6.1 431.2 45 (s fire 5¾ 6.1 415.2 (Please read the precautions on the back before filling out this page)

本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） -93- 1236477 A7 B7 五、發明說明（f/ R1This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) -93- 1236477 A7 B7 V. Description of the invention (f / R1

經濟部智慧財產局員工消費合作社印製 分析 R1 R2 Rt (min) [M+H]+ 46 6.1 431.2 47 6,24:6,17 389.2 48 5.6 444.2 49 (S火 ^〇rC 5,1 ; 5,0 442.3 50 6.4 440.2 51 / (J 6.8 498.3 52 (s火 05 6.1 385.2 53 6.5 399.2 54 (S火 6,2 ; 6,3 375.2 55 (S火 6.2 365.3 56 6.6 379.3 57 (3火 5.8 349.2 (請先閲讀背面之注意事項再填寫本頁) ▼裝--------訂·--------線I屬 1236477 A7 B7 卜、發明說明（p) 經濟部智慧財產局員工消費合作社印製 R1 化學式3 R2 分析 R1 R2 Rt (min) [M+H]+ 58 -&lt;I 6.2 365.3 59 6.8 415.1 60 x€c} 6.8 457.2 61 NO, .jy 6.6 450.1 62 (&gt; NO, 力 6.3 416.2 63 CN 6,0:6.1 396.2 64 (R&gt; 〇/ 6.1 431.2 65 (R) v 6.1 415.2 66 6.1 431.2 67 6,23:6,17 389.2 68 (R) \ Ar I 一 I 5.7 444.3 69 5,0:5,1 442.3 --------------裝---(請先閱讀背面之注意事項再填寫本頁) --線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -95 - 經濟部智慧財產局員工消費合作社印製 1236477 A7 B7 五、發明說明（f R1 L H R2 化學式3 分析 R1 R2 Rt (min) [M+H】+ 70 6.4 440.2 71 / u 6.8 498.3 72 6.1 385.2 73 (R&gt; ^j〇 6.5 399.2 74 (&gt; 6.2 365.3 75 (&gt; 6.6 379.3 76 (R) \ /V 5.8 349.2 77 (R) v /V -&lt;z 6.2 365.3 78 ;&gt;rs、， 6.8 415.1 79 6.8 457.2 (請先閱讀背面之注意事項再填寫本頁) 訂---------線！ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -96- 經濟部智慧財產局員工消費合作社印製 1236477 A/ B7 五、發明說明（？么: R1 Οςζώ 化學式4 R2 分析 R1 R2 Rt (min) 【M+H卜 1 (S) 6.2 451.2 2 (s) 6.4 496.3 3 :σ。、 ΧτΝ〇ί 6.3 466.3 4 Xr。、 6.1 421.3 5 :σ。、 7.0 477.4 6 (Χτ。、 j〇rs_ 6.5 467.3 7 (S) j5 6.5 499.2 δ (S) ^^^0、 irr&quot; 6.1 494.4 9 :σ。、 I jr 一、 5.2 522.4 10 :σ。、 Λ 6.1 465.3 11 :σ。、 ja&quot; 5.8 464.4 12 :σ。、 N02 6.6 500.3 (請先閱讀背面之注意事項再填寫本頁) ;裝 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -97- I 1236477 A7 B7 I ^ ^ 丨五、發明說明 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）Printed Analysis of Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs R1 R2 Rt (min) [M + H] + 46 6.1 431.2 47 6, 24: 6, 17 389.2 48 5.6 444.2 49 (S fire ^ 〇rC 5,1; 5 0 442.3 50 6.4 440.2 51 / (J 6.8 498.3 52 (S fire 05 6.1 385.2 53 6.5 399.2 54 (S fire 6, 2; 6, 3 375.2 55 (S fire 6.2 365.3 56 6.6 379.3 57 (3 fire 5.8 349.2 ( Please read the precautions on the back before filling out this page) ▼ Installation -------- Order · -------- Thread I belongs to 1236477 A7 B7 bu, invention description (p) Intellectual Property Bureau of the Ministry of Economic Affairs Printed by employee consumer cooperative R1 Chemical formula 3 R2 Analysis R1 R2 Rt (min) [M + H] + 58-&lt; I 6.2 365.3 59 6.8 415.1 60 x € c} 6.8 457.2 61 NO, .jy 6.6 450.1 62 (&gt; NO, force 6.3 416.2 63 CN 6,0: 6.1 396.2 64 (R &gt; 〇 / 6.1 431.2 65 (R) v 6.1 415.2 66 6.1 431.2 67 6,23: 6, 17 389.2 68 (R) \ Ar I-I 5.7 444.3 69 5,0: 5,1 442.3 -------------- install --- (please read the precautions on the back before filling this page) --line National Standard (CNS) A4 Specification (210 X 297 mm) -95-Ministry of Economy Printed by the Intellectual Property Cooperative's Consumer Cooperative 1236477 A7 B7 V. Description of the invention (f R1 LH R2 Chemical formula 3 Analysis R1 R2 Rt (min) [M + H] + 70 6.4 440.2 71 / u 6.8 498.3 72 6.1 385.2 73 (R &gt; ^ j〇6.5 399.2 74 (&gt; 6.2 365.3 75 (&gt; 6.6 379.3 76 (R) \ / V 5.8 349.2 77 (R) v / V-&lt; z 6.2 365.3 78; &rs;, 6.8 415.1 79 6.8 457.2 (Please read the notes on the back before filling this page) Order --------- line! This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) -96- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 1236477 A / B7 V. Description of the invention (?: R1 Οςζώ Chemical formula 4 R2 analysis R1 R2 Rt (min) [M + H Bu 1 (S) 6.2 451.2 2 (s) 6.4 496.3 3: σ., ΧτΝ〇ί 6.3 466.3 4 Xr., 6.1 421.3 5: σ., 7.0 477.4 6 (χτ. , J〇rs_ 6.5 467.3 7 (S) j5 6.5 499.2 δ (S) ^^^ 0, irr &quot; 6.1 494.4 9: σ., I jr one, 5.2 522.4 10: σ., Λ 6.1 465.3 11: σ. ,, ja &quot; 5.8 464.4 12: σ., N02 6.6 500.3 (please read the precautions on the back before filling this page); the size of this paper is applicable to China National Standard (CNS) A4 (210 X 297 mm) -97- I 1236477 A7 B7 I ^ ^ Ⅴ. Description of the invention The paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm)

R1 化學式4 R2 分析 R1 R2 Rt (min) (M+H]+ 13 :σ。、 々、 6.3 469.3 14 :σ。、 wj〇 6.5 465.3 15 :σ。、 νΑ 6.1 401.4 16 ，σ。、 6.2 401.3 17 !：σ。、 6.5 415.4 18 (:σ。、 6.7 429.4 19 :σ。、 X) 6,4 ; 5,9 427.4 20 :σ。、 6.0 419.3 21 (》。、 .5 6.2 451.3 22 (》。、 6.4 496.3 23 (》。、 ,ίΤ02 6.3 466.3 24 (》。、 j〇 6.1 421.3 25 (》。、 7.0 477.4 經濟部智慧財產局員工消費合作社印製 (請先閱讀背面之注意事免再填寫本頁) -98- I 1236477 A7 B7 五、發明說明 經齊郎智慧財轰咼員二消費合阼法中製 Οςί&gt;κ ^ H R2 化學式4 分析 R1 R2 Rt (min) [M+Hh 26 (》。、 6.5 467.3 27 (》。、 Br 力 6.5 499.2 28 (》。、 ίχτ&quot; 6.2 494.4 29 (:σ。、 I 》。一 5.2 522.4 30 (》。、 〆〇0 6.1 465.3 31 (》。、 5.8 464.4 32 (》。、 N〇2 6.6 500.3 33 jy 方、 6.3 469.3 34 (》。、 0 6.5 465.3 35 (》。、 、人 6.1 401.3 36 《》。、 6.2 401.3 37 Xr。、 6.5 415.3 --------------裝—— (請先閱讀背面之注意事項再填寫本頁)R1 Chemical formula 4 R2 Analysis R1 R2 Rt (min) (M + H) + 13: σ., 々, 6.3 469.3 14: σ., Wj〇6.5 465.3 15: σ., ΝΑ 6.1 401.4 16, σ., 6.2 401.3 17 !: σ., 6.5 415.4 18 (: σ., 6.7 429.4 19: σ., X) 6,4; 5,9 427.4 20: σ., 6.0 419.3 21 ("., .5 6.2 451.3 22 (" ., 6.4 496.3 23 ("., Τ02 6.3 466.3 24 (", j〇6.1 421.3 25 ("., 7.0 477.4 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, please read the precautions on the back before filling out (This page) -98- I 1236477 A7 B7 V. Description of the invention Manufactured by Qi Lang's Smart Wealth Manager 2 Consumption Combining Method Οςί &gt; κ ^ H R2 Chemical Formula 4 Analysis R1 R2 Rt (min) [M + Hh 26 ( 》, 6.5 467.3 27 (", Br force 6.5 499.2 28 (", ίχτ &quot; 6.2 494.4 29 (: σ., I). 5.2 522.4 30 (". 、 0 6.1 465.3 31 (". ,, 5.8 464.4 32 ("., No. 2 6.6 500.3 33 jy Fang, 6.3 469.3 34 ("., 0 6.5 465.3 35 ("., Person 6.1 401.3 36") ., 6.2 401.3 37 Xr., 6.5 415.3 -------------- install-(Please read the precautions on the back before filling this page)

Jaj· --線· 1236477 A7 B7 五、發明說明（”） 經濟部智慧財產局員工消費合作社印製 R1 H R2 化學式4 分析 R1 R2 Rt (min) [M+H]+ 38 (R)r^V〇、 jy 6.7 429.4 39 》。、 〆0 6,4; 5,9 427.4 40 (》。、 6.1 419.3 41 ,6 6.4 466.3 42 分。 。必 6.8 511.3 43 j〇rN。2 6.5 481.3 44 6.3 436.3 45 7.1 492.4 46 (!€r'：0 JT- 6.6 482.3 47 (!CrS：0 Βγ 6.7 514.2 48 (分。 ίχτ^ 6.6 509.3 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -100- r 1236477 A7 B7 五、發明說明（背） R1 H R2 化學式4 分析 R1 R2 Rt (min) 49 (!α':〇 jOr。」、 5.4 537.4 50 (分 X〇 6.3 480.3 51 6.4 479.3 52 (!χ/。 n〇2 6.9 515.2 53 (S^:〇 方、 6.5 484.3 54 0 6.7 480.3 55 (!α':〇 Ok 6.3 416.3 56 6.4 416.3 57 (!χ/。 6.7 430.3 58 (!Cr'：0 6.9 444.4 --------------裝—— (請先閱讀背面之注意事項再填寫本頁) 訂： 線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） -101- 1236477 at B7 五、發明說明) 經濟部智慧財產局員工消費合作社印製 R1 化學式4 H R2 分析 R1 R2 Rt (min) [M+H 卜 59 (Sja':〇 、户S〆 6,6; 6.4 442.3 60 (!α&quot;° 〆0 6.3 434.3 61 6.4 466.3 62 6.8 511.3 63 ：σ':° 6.5 481.3 64 JO 6.3 436.3 65 (：σ&quot;° 7.1 492.4 66 (:01° j〇rs_ 6.6 482.3 67 (；σ&quot;° 6.7 514.2 68 (：σ&quot;° Xr^ 6.6 509.3 (請先閱讀背面之注意事項再填寫本頁)Jaj · --line · 1236477 A7 B7 V. Description of the invention (") Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy R1 H R2 Chemical formula 4 Analysis R1 R2 Rt (min) [M + H] + 38 (R) r ^ V0, jy 6.7 429.4 39》, 〆0 6,4; 5,9 427.4 40 (”, 6.1 419.3 41, 6 6.4 466.3 42 points… must 6.8 511.3 43 j〇rN. 2 6.5 481.3 44 6.3 436.3 45 7.1 492.4 46 (! € r ': 0 JT- 6.6 482.3 47 (! CrS: 0 Βγ 6.7 514.2 48 (min. Ίχτ ^ 6.6 509.3 (please read the precautions on the back before filling this page)) This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) -100- r 1236477 A7 B7 V. Description of the invention (back) R1 H R2 Chemical formula 4 Analysis R1 R2 Rt (min) 49 (! Α ': 〇jOr. " , 5.4 537.4 50 (min X〇6.3 480.3 51 6.4 479.3 52 (! Χ /. N〇2 6.9 515.2 53 (S ^: 〇 square, 6.5 484.3 54 0 6.7 480.3 55 (! Α ': 〇Ok 6.3 416.3 56 6.4 416.3 57 (! Χ /. 6.7 430.3 58 (! Cr ': 0 6.9 444.4 -------------- install-(Please read the precautions on the back before filling out this page) Order: line -This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 χ 297 mm) -101- 1236477 at B7 V. Invention Description) Printed by R1 Chemical Formula 4 H R2 Analysis R1 R2 Rt (min) [M + H BU 59 (Sja ': 〇, household S〆6,6; 6.4 442.3 60 (! α &quot; ° 〆0 6.3 434.3 61 6.4 466.3 62 6.8 511.3 63: σ': ° 6.5 481.3 64 JO 6.3 436.3 65 (: σ &quot; ° 7.1 492.4 66 (: 01 ° j〇rs_ 6.6 482.3 67 (; σ &quot; ° 6.7 514.2 68 (: σ &quot; ° Xr ^ 6.6 509.3 (Please read the precautions on the back before filling in this page )

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -102- 1236477 A7B7 明發五This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -102- 1236477 A7B7 Mingfa 5

R1 H R2 化學式4 分析 R1 R2 Rt (min) [M+H]+ 69 j〇r。」、 5.4 537.4 70 6.3 480.3 71 6.4 479.3 72 ，〇rS:° νο2 6.9 515.2 73 方、 6.5 484.3 74 6.7 480.3 75 6.3 416.3 76 6.4 416.3 77 ：σ':° 6.7 430.4 78 (；σ&quot;° 6.9 444.4 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -103- 1236477 A7 B7 五、發明說明（（e) 經濟部智慧財產局員工消費合作杜印製 R1 H R2 化學式4 分析 R1 R2 Rt (min) 79 (：σ&quot;° 〆0 6,6; 6,3 442.3 80 (：σ&quot;° 、产s/ 6.3 434.3 (請先閱讀背面之注意事項再填寫本頁) 訂： -線 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -104- S费lari时轰肖費.乍1£中緹 1236477 A7 B7 R1 化學式5 H R2 分析 R1 R2 Rt (min) [M+H]+ 1 &quot;0 !)〇 5.4 421.1 2 (：0 5.4 421.1 3 &quot;0 5.4 421.1 4 (^0 5.4 421.1 5 (工0 5.4 421.1 6 % ；α。、 5.4 421.1 7 &quot;0 J&amp;、 I 5.3 481.1 8 j&amp;r I 5.3 481.1 9 xo 5.3 435.1 10 ：〇 xo 5.4 435.1 11 &quot;0 。:c〇 5.4 480.1 (請先閱讀背面之注意事項再填寫本頁) 裝 Ίδ. ;線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -105- 1236477 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（卜5) R1 化學式5 ^ R2 分析 R1 R2 Rt (min) [M+H 卜 23 ，0 /7〇CPa 5.6 475.1 24 (^0 5.6 475.1 25 (二0 cf3 5.5 459.1 26 % cf3 5.5 459.1 27 方、 5.4 439.1 28 ：〇 方、 5.4 439.1 29 &quot;0 5.4 409.1 30 :〇 5.4 409.1 31 &quot;0 Br 5.5 469.0 32 ：0 A Br 5.5 469.0 33 Qr 5.5 469.0 34 (：0 Br . 5.5 469.0 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(C蠢規格(21_7公爱）屬_ i.&amp; Sr £oi 时 i 肖 larkt一乍：ad 1236477 五、發明說明（丨0幻 R1 化學式5 H R2 分析 R1 R2 Rt (min) [M^H]+ 35 &quot;0 5.5 469.0 36 5.5 469.0 37 &quot;0 ：xr 5.6 459.0 38 (：0 5.6 459.0 39 :0 Cl 5.6 459.0 40 5.6 459.0 41 (二 0 1 乃。一 4.9 492.2 42 ：0 4.6 492.2 43 5.3 434.1 44 % χτ^ 5.3 434.1 45 5.1 448.1 46 ：0 /7Y 5.1 448.1 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -107- 1236477 A7 37 五、發明說明（(“/) 經濟部智慧財產局員工消費合作社印製. R1 (X^ FORMULA 5 ^ R2 Analyses R1 R2 Rt (min) [M+H 卜 47 &quot;0 5.7 447.2 46 5.7 447.2 49 5.6 479,1 50 :〇 5.6 479.1 51 ，0 /〇r°H 5.2 407.1 52 X) ^r〇H 5.2 407.1 53 OH 力。、 5.2 437.1 54 (：!0 OH 力。、 • 5.2 437.1 55 &quot;0 JO0 5.6 467.1 56 (：〇 5.6 467.1 57 Λ 5.4 405.2 58 :〇 5.4 405.2 (請先閱讀背面之注意事項再填寫本頁) .裝 i線 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -108- 1236477 五、發明說明（(〇的 R1 (XX^? H an FORMULA 5 〜 Analyses R1 R2 Rt (min) [M+H]+ 59 XTS- 5.5 437.1 60 (：0 ^rs_ 5.5 437.1 61 5.3 391.1 62 ：〇 5.3 391.1 63 5.5 435.1 64 (^0 0 5.5 435.1 65 &quot;0 刀 5.5 397.2 66 (：0 X) 5.4 397.2 67 &quot;0 5.1 355.2 68 (:¾ 5.1 355.2 69 (:0 5.2 357.2 70 ：0 5.2 357.2 I--------------^--- (請先閱讀背面之注意事項再填寫本頁) ;線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -109- 1236477 A7 B7 五、發明說明) 經濟部智慧財產局員工消費合作社印製 R1 Η ρη FORMULA 5 〜 Analyses R1 R2 Rt (min) [Μ+Η]+ 71 &quot;0 5.3 371.2 72 5.3 371.2 73 &quot;0 -V 5.3 385.2 74 ：0 5.3 385.2 75 &quot;0 νΑ 5.3 371.2 76 χι νΛ 5.3 371.2 77 &quot;0 5.3 389.1 78 ：〇 5.3 389.1 79 &quot;0 5.6 413.2 80 (：0 5.7 413.2 (請先閲讀背面之注意事項再填寫本頁) =0 · •線 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公嫠） -110-R1 H R2 Chemical Formula 4 Analysis R1 R2 Rt (min) [M + H] + 69 j〇r. ", 5.4 537.4 70 6.3 480.3 71 6.4 479.3 72, 〇rS: ° νο 2 6.9 515.2 73 square, 6.5 484.3 74 6.7 480.3 75 6.3 416.3 76 6.4 416.3 77: σ ': ° 6.7 430.4 78 (; σ &quot; ° 6.9 444.4 ( Please read the notes on the back before filling in this page) This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) -103- 1236477 A7 B7 V. Description of the invention ((e) Intellectual Property Bureau of the Ministry of Economic Affairs Employee Consumption Cooperation Du R1 H R2 Chemical Formula 4 Analysis R1 R2 Rt (min) 79 (: σ &quot; ° 〆0 6,6; 6,3 442.3 80 (: σ &quot; °, production s / 6.3 434.3 (Please read first Note on the back page, please fill in this page again) Order:-The paper size of the thread is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) -104- S fee lari when the fee is charged. 1 £ Zhongti 1236477 A7 B7 R1 Chemical formula 5 H R2 Analysis R1 R2 Rt (min) [M + H] + 1 &quot; 0!) 〇5.4 421.1 2 (： 0 5.4 421.1 3 &quot; 0 5.4 421.1 4 (^ 0 5.4 421.1 5 (Work 0 5.4 421.1 6%; α., 5.4 421.1 7 &quot; 0 J &amp;, I 5.3 481.1 8 j & r I 5.3 481.1 9 x o 5.3 435.1 10: 0xo 5.4 435.1 11 &quot; 0 :: c〇5.4 480.1 (Please read the precautions on the back before filling out this page) Decoration δ.; line · This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) -105- 1236477 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention (Bu 5) R1 Chemical formula 5 ^ R2 Analysis R1 R2 Rt (min) [M + H Bu 23, 0 / 7〇CPa 5.6 475.1 24 (^ 0 5.6 475.1 25 (0 0 cf3 5.5 459.1 26% cf3 5.5 459.1 27 square, 5.4 439.1 28: square, 5.4 439.1 29 &quot; 0 5.4 409.1 30: 〇5.4 409.1 31 &quot; 0 Br 5.5 469.0 32: 0 A Br 5.5 469.0 33 Qr 5.5 469.0 34 (: 0 Br. 5.5 469.0 (Please read the precautions on the back before filling this page) This paper size applies Chinese national standard (C stupid specification (21_7 Public love) belongs to the genus _ i. &Amp; Sr £ oi Shi i Xiao larkt at first glance: ad 1236477 V. Description of the invention (丨 0 Magic R1 Chemical formula 5 H R2 Analysis R1 R2 Rt (min) [M ^ H] + 35 &quot; 0 5.5 469.0 36 5.5 469.0 37 &quot; 0: xr 5.6 459.0 38 (: 0 5.6 459.0 39: 0 Cl 5.6 45 9.0 40 5.6 459.0 41 (2 0 1 is. 4.9 492.2 42 ： 0 4.6 492.2 43 5.3 434.1 44% χτ ^ 5.3 434.1 45 5.1 448.1 46: 0 / 7Y 5.1 448.1 (Please read the precautions on the back before filling out this page) The paper size applies to the Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) -107- 1236477 A7 37 V. Invention Description (("/" Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. R1 (X ^ FORMULA 5 ^ R2 Analyses R1 R2 Rt (min) [M + H Bu 47 &quot; 0 5.7 447.2 46 5.7 447.2 49 5.6 479,1 50: 05.6 479.1 51, 0 / 〇r ° H 5.2 407.1 52 X) ^ rOH 5.2 407.1 53 OH force., 5.2 437.1 54 (:! 0 OH force., • 5.2 437.1 55 &quot; 0 JO0 5.6 467.1 56 (: 〇5.6 467.1 57 Λ 5.4 405.2 58: 〇5.4 405.2 (Please read the precautions on the back before filling this page). Install i The size of the paper is applicable to China National Standard (CNS) A4 (210 X 297 mm) -108- 1236477 V. Description of the invention ((〇 的 R1 (XX ^? H an FORMULA 5 ~ Analyses R1 R2 Rt (min) [ M + H] + 59 XTS- 5.5 437.1 60 (: 0 ^ rs_ 5.5 437.1 61 5.3 391.1 62: 05. 3 391.1 63 5.5 435.1 64 (^ 0 0 5.5 435.1 65 &quot; 0 knife 5.5 397.2 66 (: 0 X) 5.4 397.2 67 &quot; 0 5.1 355.2 68 (: ¾ 5.1 355.2 69 (: 0 5.2 357.2 70: 0 5.2 357.2 I -------------- ^ --- (Please read the notes on the back before filling out this page); Line-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -109- 1236477 A7 B7 V. Invention Description) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy R1 R ρη FORMULA 5 ~ Analyses R1 R2 Rt (min) [Μ + Η] + 71 &quot; 0 5.3 371.2 72 5.3 371.2 73 &quot; 0 -V 5.3 385.2 74: 0 5.3 385.2 75 &quot; 0 νΑ 5.3 371.2 76 χι νΛ 5.3 371.2 77 &quot; 0 5.3 389.1 78: 05.3 389.1 79 &quot; 0 5.6 413.2 80 (: 0 5.7 413.2 (Please read the precautions on the back before filling out this page) = 0 • • The size of thread paper is applicable to China National Standard (CNS) A4 (210 X 297 cm) -110-

Claims (1)

1236477 、申請專利範圍 it名 範圍修正本 修正日期：94年3月 第88109827號專利再審查案申請專1^ 1 · 一種 具有式⑴之化合物：1236477 、 Application patent scope it name Scope amendments Date of revision: March 1994 No. 88109827 Patent reexamination case application 1 ^ 1 3 R (I) 。亥/、有式（I)之化合物之消旋-非對映異構體混合物與 光學異構物，此等之藥學上可接受的鹽類， 其中： ........表示一個任擇的鍵結； X為N或N-R4，其中當兩個任擇的鍵結存在時χ為N， 而當兩個任擇的鍵結不存在時X為N-R4 ; R】為 Η、-(CH2)m-C(〇MCH2)me、·_2)^ζ】、侧2)^〇 ^ 或(C〇-C6)烷基-C(0)-NH-(CH2)m-Z3 ; Z1係為一個選自下列群中之經任擇取代的部分： (C「C】2)烷基、苯並噻吩、苯基、萘基、苯並⑻ 呋喃基、噻吩、異噁唑基、吲哚基、3 R (I). Hai /, racemic-diastereomeric mixtures and optical isomers of compounds of formula (I), such pharmaceutically acceptable salts, where: ........ represents a Optional bond; X is N or N-R4, where χ is N when two optional bonds are present, and X is N-R4 when two optional bonds are not present; R] is Η,-(CH2) mC (〇MCH2) me, _2) ^ ζ], 2) ^ 〇 ^ or (C〇-C6) alkyl-C (0) -NH- (CH2) m-Z3; Z1 is an optionally substituted moiety selected from the group consisting of: (C "C] 2) alkyl, benzothiophene, phenyl, naphthyl, benzofluorenyl furanyl, thiophene, isoxazolyl, Indolyl, R 係為（C】-Ci2)烧基、（C〇-C6)烧基 &lt;(0)-〇-25、（(^。（^6) 烧基-C(0)-NH-(CH2)m-Z3或任擇取代的苯基； 及 1236477 申請專利範圍 z係為Η、（CVC12)烷基或（CH2)m-芳基； 係為胺基、（ci-cu)烷基胺基、N，N-二-(Cl-Cl2)垸 基胺基、_NH_c(0)_0_(CH2)m 苯基、 C(〇) 〇-(CH2)m-(C]-C6)烧基或一個選自下列群 中之、、’呈任擇取代的部分：咪唾基、吼σ定基與嗎琳基、 哌啶基、哌嗉基、咄唑啉基、呋喃基與噻吩； R3係為Η ; R4係為 Η、-C(=Y)-N(X1X2)、c(=〇)x2*x2 ; γ係為ο或s ; x 係為 f係為H或—個選自下列群中之經任擇取代的部 ::(C]-C12)烷基、((：3丨8)環烷基、(c广y烷氧基、 方虱基、(c】-c12)烷基胺基、N，冰二(c】_c】2)烷基胺 基、-CH-二-(CVC!2)烷氧基或苯基； j系為（C】C]2)烷氧基苯基 (X )n (C3-C]2)i：^ 基、_(CH丄_s_(Ci_Ci2)烧基、 (cvc12)烧基 H(C1_C12)烧基、_(CH2)m_(cl_cl2)快 基或-個選自下列群中之經任擇取代的部分：苯基、R system is (C) -Ci2) alkyl, (C0-C6) alkyl &lt; (0) -〇-25, ((^. (^ 6) alkyl) -C (0) -NH- (CH2 ) m-Z3 or an optionally substituted phenyl group; and 1236477 The scope of application for patent z is fluorene, (CVC12) alkyl or (CH2) m-aryl group; is amine group, (ci-cu) alkylamino group , N, N-di- (Cl-Cl2) fluorenylamino, _NH_c (0) _0_ (CH2) m phenyl, C (〇) 〇- (CH2) m- (C) -C6) alkyl or one And optionally selected from the following groups: imosalyl, sigma and morphinyl, piperidinyl, piperidinyl, oxazoline, furanyl, and thiophene; R3 is Η ; R4 is Η, -C (= Y) -N (X1X2), c (= 〇) x2 * x2; γ is ο or s; x is f or H or one selected from the group Optionally substituted moieties: (C) -C12) alkyl, ((: 3 丨 8) cycloalkyl, (c-y-alkoxy, fangyl, (c) -c12) alkylamino, N , Bis (c) _c] 2) alkylamino, -CH-di- (CVC! 2) alkoxy or phenyl; j is (C) C] 2) alkoxyphenyl (X) n (C3-C) 2) i: ^ group, _ (CH 丄 _s_ (Ci_Ci2) group, (cvc12) group, H (C1_C12) group, _ (CH2) m_ (cl_cl2) fast group, or one Selected from The selection of either group substituted moieties: phenyl, 二烷基胺基之烷 吱喃基、嚷吩、。比°各基”比咬基以及 Y係為Ο、S、NH或一個鍵結； R6係為Η或SCV笨基； R7係為Η、被任擇地取代以烷氧基或 基； 1236477Dialkylamino alkyl alkanyl, stilbene. The ratio of each group is more than 0, and Y is 0, S, NH or a bond; R6 is fluorene or SCV benzyl; R7 is fluorene, optionally substituted with alkoxy or group; 六、申請專利範圍 其中一個經任擇取代的部分或苯基被任擇地取代以 或多個各自選自下列群中之取代基·· C卜F、Br、I、 CF3、N02、OH、S02NH2、CN、N3、-〇CF3、（CVCn) 燒氧基、-(CHi-苯基 _(xi)n、_NH_C(MCVC6)烷基、 -S-苯基-(χΐ)η 、 -(MCH2)m_ 苯基兴χ1)η 、 烧基、-(CHOm-CCOMCVD 烧基、-0-(CH2)m-NH2、-〇-(CH2)m-NH-(CVC6)烧基、 _〇_(CH2)m-N-二-[(C「C6)烷基]以及 _(CVCi2)烷基 '(Χ^η ； X1在每次出現係各自為選自於下列群中：氫、C卜F、 Br、I、N02、OH、-CF3、-〇CF3、（CKC12)烷基、（CKC12) 烧氧基、-S'CVCd烷基、_(CH2)m-胺基、 -(CH2)m-NH-(CKC6)烧基、-(CH2)m-N-^-[(CKC6)烷 基]、-(CH2)m-苯基以及-(CH2)m-NH_(C3_C6)環烷基； m在每次出現係各自為0或一個由1至6之整數；以及 η在每次出現係各自為一個由1至5之整數。 2.如申請專利範圍第i項之化合物，其中又為1^]9 ; ；^1為 Η ; R2為-CH(CH3)2-C〇-NH-(CH2)mZ3，其中 R2之定義 中的m係為1、2或3 ; z係為咪唑基、吡啶基、嗎啉代或N，N-二-乙胺基； R5係為丙基、正丁基、正戊基、-(CH+CHCE^)-苯基、 2-硝基-3-OMe-苯基、p-t-Bu-苯基、m-OMe-苯基、 o-OMe-苯基、p-硝基-苯基、·（(：Η2)2-8-Μ^、環己基、 m-Br-苯基、p-S-Me-苯基、ρ-Ν5Ν-二曱基胺基-苯基、 -113- 1236477 六、申請專利範圍Sixth, the scope of the patent application where one of the optionally substituted moieties or phenyl groups is optionally substituted with one or more substituents each selected from the group: C, F, Br, I, CF3, N02, OH, S02NH2, CN, N3, -〇CF3, (CVCn) alkoxy,-(CHi-phenyl_ (xi) n, _NH_C (MCVC6) alkyl, -S-phenyl- (χΐ) η,-(MCH2 ) m_phenyl group x1) η, alkyl,-(CHOm-CCOMCVD alkyl, -0- (CH2) m-NH2, -〇- (CH2) m-NH- (CVC6) alkyl, _〇_ ( CH2) mN-di-[(C "C6) alkyl] and _ (CVCi2) alkyl '(χ ^ η; X1 in each occurrence is selected from the following groups: hydrogen, C, F, Br , I, N02, OH, -CF3, -〇CF3, (CKC12) alkyl, (CKC12) oxy, -S'CVCd alkyl, _ (CH2) m-amine,-(CH2) m-NH -(CKC6) alkyl,-(CH2) mN-^-[(CKC6) alkyl],-(CH2) m-phenyl, and-(CH2) m-NH_ (C3_C6) cycloalkyl; m The occurrences are each 0 or an integer from 1 to 6; and each occurrence of η is an integer from 1 to 5. 2. For the compound in the scope of application for item i of the patent application, which is 1 ^] 9 ; ^ 1 is Η; R2 is -CH (CH3) 2-C〇-NH- (CH2) mZ3 Where m in the definition of R2 is 1, 2 or 3; z is imidazolyl, pyridyl, morpholino or N, N-di-ethylamino; R5 is propyl, n-butyl, n- Amyl,-(CH + CHCE ^)-phenyl, 2-nitro-3-OMe-phenyl, pt-Bu-phenyl, m-OMe-phenyl, o-OMe-phenyl, p-nitro -Phenyl, · ((: Η2) 2-8-M ^, cyclohexyl, m-Br-phenyl, pS-Me-phenyl, ρ-N5N-diamidinoamino-phenyl, -113 -1236477 6. Scope of patent application R6係為Η ;以及R7係為Η。 3·如申請專利範圍第1項之化合物，其中 X為ΝΗ ; R1為η ; R2為苯基； 尺係為丙基、正丁基、正戊基、正庚基、新戊基、環 丙基、環己基、-(CH2)2-S-Me、苯基、-(ch2)-0-(CH2)-笨基、2-硝基-3-0Me_苯基、p-t-Bu-苯基、〇-〇Me-苯 基、m-OMe-笨基、p-〇Me-苯基、3,4,5-三-OMe-苯基、 P-丁氧基-苯基、3-乙氧基-4-曱氧基·苯基、0-硝基-笨基、p-硝基-苯基、p-〇CF3-苯基、…〇CF3_苯基、 3^4-〇me_苯基、0_F_苯基、〇-B卜苯基、m-Br苯基、 P-Br-苯基、2,4·二·C1-苯基、3,4•二 _Ci_ 苯基、 P-(3-(N5N-二曱基胺基）丙氧基）苯基、《CH2)2-S_Me、 環己基、p-(Me-CO-NH-)-苯基、p-t-Bu-苯基、p-OH-苯基、p-(S-Me)-苯基、p + S-t-Bu)-苯基、p-N，N-二曱 基胺基-苯基、m-曱基-苯基、3-〇H-4-OMe-苯基、p- 苯基·苯基R6 is Η; and R7 is Η. 3. The compound according to item 1 in the scope of patent application, wherein X is NΗ; R1 is η; R2 is phenyl; the scale is propyl, n-butyl, n-pentyl, n-heptyl, neopentyl, cyclopropyl , Cyclohexyl,-(CH2) 2-S-Me, phenyl,-(ch2) -0- (CH2) -benzyl, 2-nitro-3-0Me_phenyl, pt-Bu-phenyl 〇-〇Me-phenyl, m-OMe-benzyl, p-〇Me-phenyl, 3,4,5-tri-OMe-phenyl, P-butoxy-phenyl, 3-ethoxy 4-Amino-4-phenyl, 0-nitro-benzyl, p-nitro-phenyl, p-〇CF3-phenyl, ... CF3-phenyl, 3 ^ 4-〇me_benzene Group, 0_F_phenyl group, 0-Bbuphenyl group, m-Brphenyl group, P-Br-phenyl group, 2,4 · di · C1-phenyl group, 3,4 · di_Ci_phenyl group, P- (3- (N5N-diamidinoamino) propoxy) phenyl, "CH2) 2-S_Me, cyclohexyl, p- (Me-CO-NH-)-phenyl, pt-Bu-phenyl, p-OH-phenyl, p- (S-Me) -phenyl, p + St-Bu) -phenyl, pN, N-diamidinoamino-phenyl, m-fluorenyl-phenyl, 3 -〇H-4-OMe-phenyl, p-phenyl · phenyl no2no2 r6係為Η ;以及R7係為η。 4.如申請專利範圍第1項之化合物，其中 X為ΝΗ ; R1為Η ; R2為p-〇Me-苯基或ρ-硝基-苯基； R係為正丁基、正戊基、正己基、異丁基、環己基、 1236477The r6 line is Η; and the R7 line is η. 4. The compound according to item 1 in the scope of patent application, wherein X is NΗ; R1 is Η; R2 is p-oMe-phenyl or ρ-nitro-phenyl; R is n-butyl, n-pentyl, N-hexyl, isobutyl, cyclohexyl, 1236477 六、申請專利範圍 -(CH2)2-S-Me、苯基、m-OMe-苯基、2-硝基1〇1^一 苯基、p-石肖基-苯基、p-t-Bu-苯基、卜硫曱基_苯基、 m-Br-苯基、2_〇Me_4_二甲基胺基-苯基、卜（3_⑺，冰 二甲基胺基）丙氧基）苯基、ρ-二甲基胺基_苯基、％ 硝基-4-C1-苯基 、-(CH2)-0-(CH2)-苯基或Sixth, the scope of application for patents-(CH2) 2-S-Me, phenyl, m-OMe-phenyl, 2-nitro 1101 ^ -phenyl, p-stone-sweetyl-phenyl, pt-Bu-phenyl , Thiothiazinyl_phenyl, m-Br-phenyl, 2_Me_4_dimethylamino-phenyl, sulfonyl (3-methyl, dimethylamino) propoxy) phenyl, ρ- Dimethylamino_phenyl,% nitro-4-C1-phenyl,-(CH2) -0- (CH2) -phenyl or .〇 '0 R6係為Η ;以及R7係為Η。 5· —種於一需要激發來自於一或多種生長激素釋放抑 制因子受體亞型之同效劑作用或拮抗劑作用的個體 體内激發該作用之藥學組成物，其包括一種如申請專 利範圍第1項之化合物或該化合物之一藥學上可接受 之鹽類以及一藥學上可接受之載劑。 6· —種於一需要結合一或多種生長激素釋放抑制因子 又te亞型的個體體内來產生該結合之藥學組成物，其 包括一種如申請專利範圍第1項之化合物或該化合物 之一藥學上可接受之鹽類。 7·如申請專利範圍第5項之藥學組成物，其中該藥學組 成物係用於-需要治療下列疾病的個體··肢端肥大 症再狹乍克隆氏病（Crohn’s disease)、全身性硬化 症、外部與内部胰臟假囊腫與腹水、血管活性腸多肽瘤 (VIPoma)、胰島母細胞增殖、胰島素過多、促胃液素瘤 (gastrinoma)、佐林哲 _ 艾力松症候群（z〇llingmEiiis〇n Syndiome)、腹瀉、AIDS_相關的腹瀉、化學治療相關 1236477 、申請專利範圍 的腹瀉、硬皮病、刺激性腸症候群、胰炎、小腸阻塞、 胃食道回流、庫辛氏症候群（Cushing，s Syndr〇me)、促 性腺瘤（gonad〇tr〇Pinom)、曱狀旁腺機能亢進、突眼性 曱狀腺腫（Graves，Disease)、糖尿病性神經病變、佩吉 特氏並（Paget’s disease)、多囊卵巢病（p〇lycystk ovary disease)、癌症、癌惡病質、血壓過低、食後血壓過低、 恐慌發作、生長激素（GH)分泌性腺瘤以及促曱狀腺激 素（TSH)分泌性腺瘤。 8·如申請專利範圍第5項之藥學組成物，其中該藥學組 成物係用於一需要治療下列疾病的個體：糖尿病，高 血脂質症，胰島素不敏性，χ症候群，血管病，增殖 性視網膜病，dawn phenomenon，腎病，消化性潰瘍， 腸與皮膚的以及胰與皮膚的瘻管，傾倒症候群 (dumping syndrome)，急性或慢性胰炎與胃腸激素分 泌腫瘤，血管發生，發炎性疾病；慢性同種異體移植 排斥，血管成形術，移植物血管出血或胃腸出血。 9· 一種於一需要抑制幽門螺旋桿菌（⑽μ㈣ 之增殖的個豸來給予該抑制之藥學組成物，其包括一 種如申請專利範圍第丨項之化合物或該化合物之一藥 學上可接受之鹽類。 10. —種具有式（11)之化合物： 1236477 、申請專利範圍 R2〇 '0 R6 is Η; and R7 is Η. 5. · A pharmaceutical composition for stimulating the effect in a subject in need of stimulating a synergistic effect or an antagonist effect from one or more growth hormone release inhibiting factor receptor subtypes, including a patent application such as The compound of item 1 or a pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable carrier. 6. · A pharmaceutical composition for producing the combination in an individual who needs to combine one or more growth hormone release inhibitors and te subtypes, which includes a compound or one of the compounds as described in the first patent application scope Pharmaceutically acceptable salts. 7. The pharmaceutical composition according to item 5 of the scope of patent application, wherein the pharmaceutical composition is used for-individuals who need to treat the following diseases: acromegaly, Crohn's disease, systemic sclerosis , External and internal pancreatic pseudocysts and ascites, vasoactive intestinal polypeptide tumor (VIPoma), islet blast proliferation, hyperinsulinism, gastrinoma, zorinzer_Ellison syndrome (zollingmEiiis〇n Syndiome), diarrhea, AIDS-related diarrhea, 1236477 related to chemotherapy, patent-applicable diarrhea, scleroderma, irritable bowel syndrome, pancreatitis, small intestinal obstruction, gastroesophageal reflux, Cushing's syndrome (Cushing, s Syndr 〇me), gonadal adenoma (gonad〇tr〇Pinom), hyperparathyroidism, exophthalmoid gland adenoma (Graves (Disease), diabetic neuropathy, Paget's disease (Paget's disease), multiple Cystic ovary disease, cancer, cancer cachexia, hypotension, hypotension after eating, panic attack, growth hormone (GH) secreting adenoma, and gonadotropin Hormone (TSH) secreting adenoma. 8. The pharmaceutical composition according to item 5 of the application, wherein the pharmaceutical composition is used for an individual who needs to treat the following diseases: diabetes, hyperlipidemia, insulin insensitivity, χ syndrome, vascular disease, proliferation Retinopathy, dawn phenomenon, nephropathy, peptic ulcer, intestinal and skin and pancreatic and skin fistulas, dumping syndrome, acute or chronic pancreatitis and gastrointestinal hormone secretion tumors, angiogenesis, inflammatory diseases; chronic allogeneic Allograft rejection, angioplasty, graft vascular bleeding or gastrointestinal bleeding. 9. A pharmaceutical composition for administering the inhibition of Helicobacter pylori (⑽μ㈣'s proliferation), which comprises a compound such as the scope of application for patent application or a pharmaceutically acceptable salt of the compound 10. —A compound with formula (11): 1236477, patent application scope R2 (II) 該具有式（II)之化合物之消旋-非對映異構體混合物 與光學異構物，此等之藥學上可接受的鹽類， 其中 --------表示一個任擇的鍵結； J1係為N-R6或S ; J2係為 N-R1、0 或 S ; X係為N或N-R4，其中當兩個任擇的鍵結存在時X為 N，而當該等任擇的鍵結不存在時X為N-R4; R1 為 Η、-(CHdm-CCOHCHJm-Z1 、-(CHJm-Z1 、 -(CHJm-O-Z1 或（CVC6)烷基-C(0)-NH-(CH2)m-Z3 ; z1係為一個選自下列群中之經任擇取代的部分： (ίν(:12)烷基、苯並[b]噻吩、苯基、萘基、苯並[b] 呋喃基、σ塞吩、異噁唑基、吲哚基、(II) the racemic-diastereomeric mixture and optical isomers of the compound of formula (II), such pharmaceutically acceptable salts, where -------- represents a Optional bond; J1 is N-R6 or S; J2 is N-R1, 0 or S; X is N or N-R4, where X is N when two optional bonds are present, And when these optional bonds do not exist, X is N-R4; R1 is Η,-(CHdm-CCOHCHJm-Z1,-(CHJm-Z1,-(CHJm-O-Z1, or (CVC6) alkyl- C (0) -NH- (CH2) m-Z3; z1 is an optionally substituted moiety selected from the group: (ίν (: 12) alkyl, benzo [b] thiophene, phenyl, Naphthyl, benzo [b] furanyl, σ-phene, isoxazolyl, indolyl, R2係為（CKC12)烷基、（CVC6)烷基-c(o)-〇-z5、（CVC6) 烷基-C(〇）-NH-(CH2)m-Z3或任擇取代的苯基； Z5係為Η、（C「C12)烷基或（CH2)m-芳基； 1236477 申請專利範圍 3 z係為胺基、（C「C12)烷基胺基、N，N-二-(c]-c12)垸 基胺基、-NH-C(0)-0-(CH2)m-苯基、 -ΝΗ·ί：(〇)-〇-((：Η2)ηΊ-(ίν(：6)烷基或一個選自下列群 中之經任擇取代的部分··苯基、味σ坐基、。比咬基與嗎 林基、。辰咬基、旅嗉基、咐唑琳基、呋喃基與嚷吩，· R係為Η、（CrCO烷基、或經任擇取代的苯基； R4係為 Η、、C(=0)X2或 X2 ; y係為〇或s ; X2係為 H或-(CH^-Y^X3; X3係為H或一個選自下列群中之經任擇取代的部 刀’（Ci-C丨2)烷基、（C3-C8)環烷基、（Cl_Ci2)烷氧基、 芳氧基、（CVC〗2)烷基胺基、N,N_:_(Ci_Ci2)烷基胺 基、-CH-二-(cvCu)烷氧基或苯基； R5與R8各自選自於下列群中：H、(C丨_Ci2)烷基、 -(CHmcH2)m-苯基_(χ1)η、（C3_Ci2)環炫基、 (c3-c12)環炔基、_(CH2)m_s_(Ci_c〗2)烷基、（Μη) 烧基-s-s-(Cl-Cl2)烧基、（CH2)m_(Ci_c〗2)炔基以及一 個選自下料巾之靠擇取代的部分：笨基、咬喃 基、噻吩、吡 ，但有條件 略基、吡啶基以及 是R5與R8不得同時為Η ; 起 或R5與R8和其等所連接之碳原子 1236477 六、申請專利範圍 螺狀（C4-CI2)環烷基R2 is (CKC12) alkyl, (CVC6) alkyl-c (o) -〇-z5, (CVC6) alkyl-C (〇) -NH- (CH2) m-Z3 or optionally substituted phenyl Z5 is fluorene, (C "C12) alkyl or (CH2) m-aryl; 1236477 Application for patent scope 3 z is amine, (C" C12) alkylamino, N, N-di- ( c] -c12) fluorenylamino, -NH-C (0) -0- (CH2) m-phenyl, -NΗ · ί: (〇) -〇-((: Η2) ηΊ- (ίν (: 6) Alkyl or an optionally substituted moiety selected from the group consisting of: · phenyl, sigma, phenyl, phenyl, and morphinyl, phenyl, phenyl, and zoline Furanyl and stilbene, · R is Η, (CrCO alkyl, or optionally substituted phenyl; R4 is Η, and C (= 0) X2 or X2; y is 0 or s; X2 Is H or-(CH ^ -Y ^ X3; X3 is H or an optionally substituted motif '(Ci-C 丨 2) alkyl, (C3-C8) cycloalkane selected from the group (Cl_Ci2) alkoxy, aryloxy, (CVC〗 2) alkylamino, N, N _: _ (Ci_Ci2) alkylamino, -CH-di- (cvCu) alkoxy or phenyl R5 and R8 are each selected from the group consisting of: H, (C 丨 _Ci2) alkyl,-(CHmcH2) m-phenyl_ (χ1) η, (C3_Ci2) cyclohexyl, (c3-c12) cycloalkynyl, _ (CH2) m_s_ (Ci_c〗 2) alkyl, (Μη) alkyl-ss- (Cl-Cl2) alkyl, (CH2) m_ (Ci_c〗 2) alkynyl and a selected part selected from the feeding towel: benzyl, sulfanyl, thiophene, pyridine, but the conditional acryl, pyridyl, and R5 and R8 must not be Η at the same time ; Or R5 and R8 and their connected carbon atoms 1236477 Six, patent application scope Spiral (C4-CI2) cycloalkyl N-A-B-J3 Y1係為0、S、NH或一個鍵結； A係為一個鍵結、—ccu、_c(〇)〇-、-C(〇)nh ε(3)ΝΗ_ 或-S02-; B係為一個鍵結或_(CH2)cr，其中q係為一個由i至6之 整數；NAB-J3 Y1 is 0, S, NH or a bond; A is a bond, -ccu, _c (〇) 〇-, -C (〇) nh ε (3) NΗ_ or -S02-; B Is a bond or _ (CH2) cr, where q is an integer from i to 6; J係為Η、（C〗-C6)烷基、經任擇取代的苯基、經任擇 取代的雜芳基或N(R9RW)，其中化9與以1〇各自選自於下 列群中：（CKC6)烧基以及經任擇取代的苯基，或R9 與R1G和其等所連接之氮原子一起形成一個含有R9與 R1G所連接之氮原子的具有5至8個成員之環，其中該 環的成員中之一者可任擇地為一個氧原子*NRn，其 中 R11 為（CVC6)烷基、-c(〇)-(cvc6)烷基、 -C(0)-N(V1V2) ^J is fluorene, (C〗 -C6) alkyl, optionally substituted phenyl, optionally substituted heteroaryl, or N (R9RW), wherein H 9 and H 10 are each selected from the following groups : (CKC6) alkyl and optionally substituted phenyl, or R9 together with R1G and the nitrogen atom to which they are attached to form a ring having 5 to 8 members containing the nitrogen atom to which R9 and R1G are attached, where One of the members of the ring is optionally an oxygen atom * NRn, where R11 is (CVC6) alkyl, -c (〇)-(cvc6) alkyl, -C (0) -N (V1V2) ^ -CPhNCVW2)或經任擇取代的-苯基-(C(rC6)烷基，其 中V1與V2各自選自於下列群中：η、（C「C12)烷基或 經任擇取代的-苯基-(C(rC6)烷基； R6係為Η或S02-苯基； R7係為 Η、cn、F、Br、I、CF3、N〇2、OH、S02NH2、 CN、N3、-OCF3、（CVCu)烷氧基、-(CH2)nl-苯基-(X】）n、 -NH-CCKCVC6)烷基、-S-(CVC12)烷基、各苯基 -(X1),、-0-(CH2)m_ 苯基-(X1)， 烷基、-(CHDm-qOHCVCO烷基、-0-(CH2)m-NH2、 •m 1236477 六、申請專利範圍.〇-(CH2)m-NH-(CKC6)^ ^ &gt; -〇-(CH2)m-N-^-[(C1-C6) 烧基]以及-(C〇-Ci2)烧基-(χ1、； 其中一個經任擇取代的部分或苯基被任擇地取代以 一或多個各自選自下列群中之取代基：C卜F、Br、I、 CF3、N〇2、OH、S02NH2、CN、N3、-0CF3、（CKC12) 烷氧基、-(CH2)m-苯基-(χ、、-NH-C〇_(Ci_C6)烷基、 Ι((ν(312)烷基、-s-苯基-(χ1、、-0_(CH2)m_ 苯基 -(Χ1)^ 、 -πΗ2)ηι&lt;(0)-〇-((ν(：6)烧基、 -(CHJm-CCOHCVCd 烷基、-0-(CH2)m-NH2、 -CKCH2)m-NH-(CrC6)烧基、-〇-(CH2)m-N-二-[(CKC6) 烷基]以及_(C〇-Ci2)烷基-(X1^ ; X1在每次出現係各自為選自於下列群中··氫、C卜F、 Br、I、N02、OH、-CF3、-OCF3、（CrCu)烷基、（Cl-Cl2) 烧氧基、|(Cl_C6)烷基、-(CH2)m•胺基、 -(CH2)m-NH-(Cl-C6)烧基、-(CH2)m-N_:_[(Cl_C6)貌 基]、-(CH2)m•苯基以及 _(cH2)m-NH-(C3-C6)環烧基； m在每次出現係各自為0或一個由1至6之整數；以及 η在每次出現係各自為一個由1至5之整數。 11.如申請專利範圍第1〇項之化合物，其具有下式： 420 1236477 申請專利範圍-CPhNCVW2) or optionally substituted -phenyl- (C (rC6) alkyl, wherein V1 and V2 are each selected from the group consisting of: η, (C "C12) alkyl or optionally substituted -benzene -(C (rC6) alkyl); R6 is fluorene or S02-phenyl; R7 is fluorene, cn, F, Br, I, CF3, No2, OH, S02NH2, CN, N3, -OCF3, (CVCu) alkoxy,-(CH2) nl-phenyl- (X)) n, -NH-CCKCVC6) alkyl, -S- (CVC12) alkyl, each phenyl- (X1) ,, -0 -(CH2) m_phenyl- (X1), alkyl,-(CHDm-qOHCVCO alkyl, -0- (CH2) m-NH2, • m 1236477) 6. Application for patent scope. 0- (CH2) m-NH -(CKC6) ^ ^ &gt; -〇- (CH2) mN-^-[(C1-C6) alkyl] and-(C〇-Ci2) alkyl- (χ1; one of the optionally substituted moieties Or phenyl is optionally substituted with one or more substituents each selected from the group consisting of C, F, Br, I, CF3, No2, OH, S02NH2, CN, N3, -0CF3, (CKC12 ) Alkoxy,-(CH2) m-phenyl- (χ ,, -NH-C0_ (Ci_C6) alkyl, Ι ((ν (312) alkyl, -s-phenyl- (χ1 ,, -0_ (CH2) m_phenyl- (χ1) ^, -πΗ2) η &lt; (0) -〇-((ν (: 6) alkyl,-(CHJm-CCOHCVCd alkyl, -0- (CH2) m - NH2, -CKCH2) m-NH- (CrC6) alkyl, -0- (CH2) mN-di-[(CKC6) alkyl] and _ (C〇-Ci2) alkyl- (X1 ^; X1 in each The next occurrences are each selected from the group consisting of hydrogen, C, F, Br, I, N02, OH, -CF3, -OCF3, (CrCu) alkyl, (Cl-Cl2) oxy, and ( Cl_C6) alkyl,-(CH2) m • amino,-(CH2) m-NH- (Cl-C6) alkyl,-(CH2) m-N _: _ [(Cl_C6) morphyl],-(CH2 m) phenyl and _ (cH2) m-NH- (C3-C6) cycloalkyl; m is each 0 or an integer from 1 to 6 in each occurrence; and η is each in each occurrence An integer from 1 to 5. 11. The compound of item 10 in the patent application scope has the following formula: 420 1236477 patent application scope 其中 R3係為Η或甲基； R4係為Η或甲基； R5係為Η、甲基、乙基、丁基、戊基或己基； R8係為乙基、丁基、戊基、己基或環己基； 或R5與R8與其等所連接之碳原子一起形成螺狀環己 基、螺狀環庚基、螺狀金剛烷基Where R3 is fluorene or methyl; R4 is fluorene or methyl; R5 is fluorene, methyl, ethyl, butyl, pentyl or hexyl; R8 is ethyl, butyl, pentyl, hexyl or Cyclohexyl; or R5 and R8 together with the carbon atoms to which they are attached form a spiro cyclohexyl, spiro cycloheptyl, spiro adamantyl 其中A係為一個鍵結或_C(0)0_ ; b係為一個鍵結、 -ch2-或-(CH2)2-; 係為Η或苯基；以及 R7係為Η、Me、F、C卜0Η、4曱基或小CH2-苯基。 12·如申請專利範圍第^項之化合物，其中： R3、R4與R7各自為氫 R5與R8—起形成Where A is a bond or _C (0) 0_; b is a bond, -ch2- or-(CH2) 2-; is fluorene or phenyl; and R7 is fluorene, Me, F, C 0 0 Η, 4 曱 yl or small CH2-phenyl. 12. The compound according to item ^ in the scope of patent application, wherein: R3, R4 and R7 are each hydrogen and R5 and R8 form together 以及 421- 1236477 t、申請專利範圍 咪唑基係居於R-構形； R3、R4與R7各自為氫And 421-236477 t, the scope of patent application imidazolyl is in the R-configuration; R3, R4 and R7 are each hydrogen 及咪唑基係居於R-構形； * N R3、R4與R7各自為氫，R5與R8 —起形成、~^ 以 及咪嗤基係居於R-構形； Γ~\ * S R3、R4與R7各自為氫，R5與R8—起形成'~^以及 咪唑基係居於R-構形，或其氯化氫鹽； R3係為甲基，R4與R7各自為氫，R5與R8各自為正丁 基，且味σ坐基係居於R-構形；And imidazolyl are in the R-configuration; * N R3, R4 and R7 are each hydrogen, R5 and R8 form together, ~ ^ and the imidazolyl are in the R-configuration; R7 is each hydrogen, R5 and R8 together form '~ ^ and the imidazolyl system is in the R-configuration, or its hydrogen chloride salt; R3 is methyl, R4 and R7 are hydrogen, R5 and R8 are n-butyl , And the flavor σ sitting system resides in the R-configuration; R3、R4與R7各自為氫，R5與R8—起形成* 以及 咪唑基係居於R-構形，或其氯化氫鹽； R3與R4各自為氫，R7為6-0-CH2-苯基，R5與R8各自為 正丁基，且咪唑基係為S-構形與R-構形之消旋混合 物；/~\ * N-COOEt R3、R4與R7各自為氫，R5與R8 —起形成~/ 以及咪唑基係居於R-構形，或其氯化氫鹽； 422 1236477 申請專利範圍 R3、R4與R7各自為氫，y與rl起形成\—广_2)2-苯基 以及咪唑基係居於R_構形； R3與V各自為氫，甲基，自為正丁基且 咪σ坐基係居於R-構形； R3與R4各自為氫，以7_氟基，r、r8各自為正戍 基’且坐基係Μ•構形與反·'構形之消旋混合物； R、R4與R7各自為氫，r^r8各自為正己基，且咪唑 基係居於R-構形； R R與R各自為氫，R5為氫，而r8為居於構形之 己3基以及味唾基係居於R_構形，或其延胡索酸鹽； R、R與R7各自為氫’r、r8各自為正丁基，以及咪 嗤基係居於R-構形，或其延胡索酸鹽；R3, R4 and R7 are each hydrogen, R5 and R8 together form * and the imidazolyl group is in the R-configuration, or its hydrogen chloride salt; R3 and R4 are each hydrogen, R7 is 6-0-CH2-phenyl, R5 And R8 are each n-butyl, and the imidazolyl is a racemic mixture of S-configuration and R-configuration; / ~ \ * N-COOEt R3, R4 and R7 are each hydrogen, R5 and R8 form together ~ / And the imidazolyl group resides in the R-configuration, or its hydrogen chloride salt; 422 1236477 The scope of the patent application R3, R4, and R7 are each hydrogen, and y and rl form a —- 2 — 2-phenyl group and the imidazolyl group R_ configuration; R3 and V are each hydrogen, methyl, they are n-butyl and the imide sigma group is in the R-configuration; R3 and R4 are each hydrogen, with 7-fluoro group, and r and r8 are each The ortho group is a racemic mixture of the M • configuration and the anti- ′ configuration; R, R4 and R7 are each hydrogen, r ^ r8 is n-hexyl, and the imidazolyl group is in the R-configuration; RR and R are each hydrogen, R5 is hydrogen, and r8 is a hexyl group in the configuration, and sialyl is in the R_ configuration, or its fumarate; R, R, and R7 are each hydrogen'r, r8, respectively Is n-butyl, and imidino is in the R-configuration, Or fumarate; R R與R各自為氫，r^r8 —起形成、_^以及〇米峰 基係居於R-構形； R/、R4與R7各自— 5 為乳，R與尺各自為正丁基，且咪唑 基係居於S-構形； 為乙基，且咪唑基 係居於R-構形； R3、R4與R7各自&amp;斤 5 c ^ 為虱，R與R8各自為正戊基，且咪唑 基係居於R-構形. R3與R4各自為梟 a ’R為卜曱基，…與…各自為正丁 -— 42S 1236477RR and R are each hydrogen, r ^ r8 is formed together, _ ^ and 0-meter peak groups are in the R-configuration; R /, R4, and R7 are each — 5 is milk, R and ruler are each n-butyl, and Imidazolyl is in the S-configuration; is ethyl, and imidazolyl is in the R-configuration; each of R3, R4, and R7 &amp; 5 c ^ is lice, R and R8 are each n-pentyl, and imidazolyl It is in the R-configuration. R3 and R4 are 枭 a 'R is Bu 曱 ji, ... and ... are n-Ding-42S 1236477 六、申請專利範圍 基，且咪唑基係為S-構形# 3 4 ^與1構形之消旋混合物； R與R各自為氫，尺7為7氣 8 勺/乱基，R5與R8各自為正丁 基’且味唾基係為S -構开彡盘 3 4 再开/與^構形之消旋混合物； R與R各自為氫，r7為6 勺0甲虱基，R5與R8各自為正丁 基’且味唾基係為S _構开彡 ,4 再肜與R-構形之消旋混合物； R與R各自為氫，r7為〜 &amp; 為6_羥基，R5與R8各自為正丁 基’且味唾基係為S -構形盘R 傅化與R-構形之消旋混合物； R3與R4各自為氫，r7為 為6-氣基，R5與R8各自為正丁 基’且咪唾基係為S -構形盘r 再I興R_構形之消旋混合物，或 其氯化氫鹽； R3與R4各自為氫，R、8_甲基，_r8各自為正丁 基，且㈣基係為S構形與R_構形之消旋混合物； R與R各自為氫’r、6_甲基，及5與&amp;8各自為正戊 基，且味唾基係為8構形與L構形之消旋混合物；或 R與R各自為氫’ r、6•氯基，汉5與&amp;8各自為正丁 基且米唾基係為S-構形與【構形之消旋混合物，或 其氯化氫鹽。 13_如申請專利範圍第12項之化合物，其中： R、R與R各自為氫，R5為氳，而r8為居於s_構形之 己基，以及咪唑基係居於R-構形，或其延胡索酸鹽； R、R與R各自為氫，R5與R8各自為正丁基，以及咪 唑基係居於R-構形，或其延胡索酸鹽； 424 123()477 、申請專利範圍6. The scope of the patent application, and the imidazolyl system is a racemic mixture of S-configuration # 3 4 ^ and 1 configuration; R and R are each hydrogen, ruler 7 is 7 gas 8 scoop / random group, R5 and R8 Each is n-butyl 'and the sialyl group is a racemic mixture of the S-constructed reopening / reconstructed / reconstructed configuration; R and R are each hydrogen, r7 is 6 scoops of 0-methyl, and R5 and R8 is n-butyl ', and the sialyl group is S_configuration, a racemic mixture of 4 and R-configuration; R and R are each hydrogen, r7 is ~ &amp; is 6-hydroxyl, R5 And R8 are each n-butyl 'and the sialyl group is a racemic mixture of R-configuration and R-configuration; R3 and R4 are each hydrogen, r7 is 6-amino, R5 and R8 Each is n-butyl 'and the imidyl group is a racemic mixture of S-configuration disk r and R-configuration, or a hydrogen chloride salt thereof; R3 and R4 are each hydrogen, R, 8-methyl, and _r8 Each is n-butyl, and the fluorenyl system is a racemic mixture of the S configuration and the R_ configuration; R and R are each hydrogen'r, 6-methyl, and 5 and &amp; 8 are each n-pentyl, And the sialyl group is a racemic mixture of the 8 configuration and the L configuration; or R and R are hydrogen 'r, 6 • Chloro, Han 5 and &amp; 8 are each n-butyl and Misalyl is a racemic mixture of S-configuration and [configuration, or its hydrogen chloride salt. 13_ The compound according to item 12 of the scope of patent application, wherein: R, R and R are each hydrogen, R5 is fluorene, and r8 is a hexyl group in the s_ configuration, and the imidazolyl group is in the R-configuration, or Fumarate; R, R, and R are each hydrogen, R5 and R8 are each n-butyl, and imidazolyl is in the R-configuration, or its fumarate; 424 123 () 477, scope of patent application R3、R4與R7各自為— 今7乳，R5盥Μ . 、 / ㈣係居純，形； 起形成…及 R R與R各自為氫，〜 基係居於S-構形； 、 自為正丁基，且咪唑 R3、R4與R7各自為氫R3, R4, and R7 are each — Jin 7 milk, R5, M,, / ㈣ are pure, shaped; form… and RR and R are each hydrogen, ~ the base is in the S-configuration; And each of the imidazoles R3, R4 and R7 is hydrogen 係居於R-構形；^ ，、R各自為乙基，且咪唑基 R3、R4與R7各自為 基係居於R-構形’广州各自為正戊基’且°米°坐 =4糾7各自為氫，以甲基⑽為環己基，且 咪唾基係居於R-構形； R與R4各自為氫，R7為 馬6-甲基，R5與R8各自為正丁 基，且味唾基係為s-構形與R_構形之消旋混合物；或It is in the R-configuration; ^, and R are each ethyl, and the imidazolyl groups R3, R4, and R7 are each in the R-configuration, 'Guangzhou is n-pentyl', and ° m ° = 4 Each is hydrogen, with methyl fluorene as cyclohexyl, and the imidyl group is in the R-configuration; R and R4 are each hydrogen, R7 is methyl 6-methyl, R5 and R8 are each n-butyl, and sial The base system is a racemic mixture of s-configuration and R_-configuration; or 各自為氫，以7_氟基，r%r8各自為正丁 基’且。米唾基係為S·構形與R_構形之消旋混合物； R與R各自為氫’R為&quot;氧基，r、rS各自為正丁 基，且味哇基係為S-構形與R•構形之消旋混合物； R與R各自為氫，R為6-羥基，…與尺8各自為正丁 基，且咪唑基係為S-構形與R_構形之消旋混合物； R與R各自為氫’ R為6 -氣基，反5與]^各自為正丁 基，且咪唑基係為S-構形與構形之消旋混合物，或 其氯化氫鹽； R3與R4各自為氫，R7為81基，R5與V各自為正丁 •m 1236477 、申凊專利範圍 基’且㈣基係為S·構形與R R3與R4各自為氫，R、…，r5:::5物’· 基’且咪唾基係為S_構形盘〃、R各自為正戍 及 料與R-構形之消旋混合物’·以 R3與R4各自為氫，r7 々虱R為6-乳基，…與…各自 基，且咪唑基係為3-構 馮正丁 --種於-需要激發來自; 制因子受體亞型之同效劑作用;；f長激素釋放抑 -内、紗w 沁作用或拮抗劑作用的個體 月旦内激發该作用之藥學組成物，其包括—種如申 :範圍第10項之化合物或該化合物之一藥學上二妾 受之鹽類以及一藥學上可接受之載劑。 15.:種於-需要結合—或多種生長激素釋放抑制因子 受體亞型的個體體内來產生該結合之藥學組成物，其 包括-種如申請專利範圍第10項之化合物或該化合 物之一藥學上可接受之鹽類。 16•如申請專利範圍第14項之藥學組成物’其中該藥學組 成物係用於一需要治療下列疾病的個體：肢端肥大 症再狹乍克隆氏病（Crohn’s disease)、全身性硬化 症、外部與内部胰臟假囊腫與腹水、血管活性腸多肽瘤 (VIPoma)、胰島母細胞增殖、胰島素過多、促胃液素瘤 (gastrinoma)、佐林哲-艾力松症候群（z〇mnger_miis〇I1 Syndrome)、腹瀉、AIDS-相關的腹瀉、化學治療相關 的腹瀉、硬皮病、刺激性腸症候群、胰炎、小腸阻塞、 月良道回 &gt;爪、庫辛氏症候群（Cushing’ s Syndrome)、促 ηβ 1236477Each is hydrogen, 7-fluoro group, and r% r8 are each n-butyl group. The sialyl system is a racemic mixture of the S configuration and the R configuration; R and R are each hydrogen, R is &quot; oxy, r and rS are each n-butyl, and the taste is S- A racemic mixture of the configuration and the R configuration; R and R are each hydrogen, R is 6-hydroxyl, ... and n8 are each n-butyl, and the imidazolyl system is the S-configuration and R_ configuration. Racemic mixtures; R and R are each hydrogen, R is 6-gas radical, trans 5 and ^ are n-butyl, and imidazolyl is a racemic mixture of S-configuration and configuration, or a hydrogen chloride salt thereof ; R3 and R4 are each hydrogen, R7 is 81 group, R5 and V are n-butyl • m 1236477, Shen's patent scope group 'and the fluorene group is S · configuration and R R3 and R4 are hydrogen, R, …, R5 ::: 5, and the sialyl group is the S_configuration disk, R is a racemic mixture of the material and R-configuration, and R3 and R4 are each hydrogen , R7 ticks R is 6-lactyl, ... and ... each group, and the imidazolyl group is 3-construction Feng Zhengding-species-need to excite from; the effect of isoforms of factor receptor subtypes; f long Individuals with hormone-releasing-inhibitory, endogenous, or antagonistic effects Excitation effect of the pharmaceutical composition, comprising - a species such as Shen: concubines by two or one of the salts of the compounds scope of the compounds as item 10 and a pharmaceutically acceptable carrier, a pharmaceutically on. 15 .: A pharmaceutical composition that is produced in an individual that requires binding—or multiple growth hormone release inhibitor receptor subtypes—to produce the combined pharmaceutical composition, including a compound such as the scope of application for item 10 or the compound A pharmaceutically acceptable salt. 16 • If the pharmaceutical composition of the scope of application for item No. 14 is used, wherein the pharmaceutical composition is used for an individual who needs to treat the following diseases: acromegaly, Crohn's disease, systemic sclerosis, External and internal pancreatic pseudocysts and ascites, vasoactive intestinal polypeptide tumor (VIPoma), islet blast proliferation, hyperinsulinism, gastrinoma, zolinger-Elisson syndrome (zomger_miis〇I1 Syndrome ), Diarrhea, AIDS-related diarrhea, chemotherapy-related diarrhea, scleroderma, irritable bowel syndrome, pancreatitis, obstruction of the small intestine, lunar tract &gt; claw, Cushing's Syndrome, ηβ 1236477 六、申請專利範圍 性腺瘤（gonadotropinom)、甲狀旁腺機能亢進、突眼性 甲狀腺腫（Graves，Disease)、糖尿病性神經病變、佩吉 特氏並（Paget’s disease)、多囊卵巢病（p〇lycystic 〇vary disease)、癌症、癌惡病質、血壓過低、食後血壓過低、 〜、作、生長激素（gh)分泌性腺瘤以及促甲狀腺激 素（TSH)分泌性腺瘤。 17.如申請專利範圍第14項之藥學組成物，其中該藥學組 成物係用於一需要治療下列疾病的個體：糖尿病，高 血脂質症，胰島素不敏性，X症候群，血管病，增殖 性視網膜病，dawn phenomen〇n，腎病，消化性潰瘍， 腸與皮膚的以及胰與皮膚的瘻管，傾倒症候群 (dumpmg syndr〇me)，急性或慢性胰炎與胃腸激素分 /必腫瘤i官發生’發炎性疾病；慢性同種異體移植 排斥血&amp;成形術，移植物血管出血或胃腸出血。 1 8 · -種於-需要抑制幽門螺旋桿菌（触⑽咖⑽㈣ 之增殖的個體來給予該抑制之藥學組成物，其包括一 種如申請專利範圍第_之化合物或該化合物之-藥學上可接受之鹽類。 19. -種方；-需要阻斷鈉通道的個體來給予該阻斷之藥 學組成物，其# # ^ ^ ^ ^ 、包括一種如申請專利範圍第1項之化合 20. 物或該入化合物之-藥學上可接受之鹽類。 種方、而要阻斷鈉通道的個體來給予該阻斷之藥 學組成物，其&amp; b ^ ^ ^ 、括一種如申^專利範圍第1 〇項之化合 物或該化合物之一藥學上可接受之鹽類。 427 1236477 六、申請專利範圍 轉，體來 22 :=合，該化合物之-藥學上可接受」鹽:,1 .=1要緩解神經病變性疼痛的 := 學組成物’其包括-種如申請專利範圍第i。 23 -、種仰勿m合物之—藥學上可接受之鹽類。 (、用作為-局部麻醉劑之藥學組成物，並包括一 :一物 _一-藥 24· -種供用作為一局部麻醉劑之藥學組成物，其包括一 種如申請專利範圍第10項之化合物或該化合物之一 藥學上可接受之鹽類。 25·-種於一需要治療任一種在病因學上涉及到麩胺酸 孤釋出之病理子、疾病或臨床病狀的個體來給予該治 療之藥予組成物，其包括一種如申請專利範圍第工項 之化合物或該化合物之一藥學上可接受之鹽類。 26· —種於一需要治療任一種在病因學上涉及到麩胺酸 鹽釋出之病理學、疾病或臨床病狀的個體來給予該治 療之藥學組成物，其包括一種如申請專利範圍第10 項之化合物或該化合物之一藥學上可接受之鹽類。 27.如申請專利範圍第25項之藥學組成物，其中該病理 學、疾病或臨床病狀係選自於下列群中··精神病學疾 病、激素病狀、代謝引起的腦損害、亞硫酸鹽氧化酶 不足、與肝衰竭有關的肝性腦病、嘔吐，痙攣，癲癇、 申請專利範圍 耳鳴，疼痛以及藥物濫用與戒斷。 申請專利範圍第26項之藥學組成物，其中該病理 學、疾病或臨床病狀係選自於下列群中：精神病學疾 病、激素病狀、代謝引起的腦損冑、亞硫酸鹽氧化酶 不足、與肝衰竭有關的肝性腦病、嘔吐，瘦攣，癲癇、 耳鳴，疼痛以及藥物濫用與戒斷。 29·-種於-需要治療任一種涉及神經元損害之病理學 的個體來給予該治療之藥學組成物，其包括—種如申 請專利範圍第1項之化合物或該化合物之一藥學上可 接受之鹽類。 30. —種於一需要治療任一種涉及神經元損害之病理學 的個體來給予該治療之藥學組成物，其包括一種如申 請專利範圍第10項之化合物或該化合物之一藥學上 可接受之鹽類。 3 1 ·如申請專利範圍第2 9項之藥學組成物，其中該病理學 係選自於下列群中··阿滋海默氏症，杭丁頓氏症或帕 金森氏症，病毒（包含HIV)誘發的神經退化，肌萎縮 性脊髓側索硬化症（ALS)，核上的癱瘓（supra-nuclear palsy)，下橄欖體橋腦小腦萎縮（〇pCA)，以及環境與 外源性神經毒素之作用。 32·如申請專利範圍第3〇項之藥學組成物，其中該病理學 係選自於下列群中··阿滋海默氏症，杭丁頓氏症或帕 金妹氏症，病毒（包含HI V)誘發的神經退化，肌萎縮 性脊w側索硬化症（ALS)，核上的癱瘓，下撖欖體橋 1236477 六 申請專利範圍 磁]、腦萎縮（OPCA) ’以及環声彳L ^ J 衣兄與外源性神經毒素之 作用。 33. 34. ，種於-需要治療心律不齊的個體來給予該治療之 藥學組成物’丨包括-種如申請專利範圍第i項之化 合物成該化合物之一藥學上可接受之鹽類。 齊的個體來給予該治療之 種於一需要治療心律不 藥學組成物，其包括一種如申嗜直毛丨^ m &gt; 永 T °月專利範圍第10項之化 合物或該化合物之一藥學上可接受之鹽類。 35· /種於一需要治療癲癇的個體來給予該治療之藥學 組成物’其包括-種如申請專利範圍第】項之化合物 戒該化合物之一藥學上可接受之鹽類。 36· —種於一需要治療癲癇的個體來给予該治療之藥學 組成物’其包括一種如申請專利範圍第1〇項之化合: 戒該化合物之一藥學上可接受之鹽類。Sixth, the scope of application for patents: gonadotropinom, hyperparathyroidism, exophthalmic goiter (Graves, Disease), diabetic neuropathy, Paget's disease, polycystic ovary disease (p 〇lycystic 〇vary disease), cancer, cancer cachexia, low blood pressure, low blood pressure after meals, operation, growth hormone (gh) secreting adenoma, and thyroid stimulating hormone (TSH) secreting adenoma. 17. The pharmaceutical composition according to item 14 of the application, wherein the pharmaceutical composition is used for an individual in need of treatment of the following diseases: diabetes, hyperlipidemia, insulin insensitivity, syndrome X, vascular disease, proliferative Retinopathy, dawn phenomen〇n, nephropathy, peptic ulcer, intestinal and skin as well as pancreatic and skin fistulas, dumpmg syndrome, acute or chronic pancreatitis with gastrointestinal hormones / malignant tumors' Inflammatory disease; chronic allograft rejection & angioplasty, graft vascular bleeding or gastrointestinal bleeding. 1 8 ·-Species-need to inhibit the proliferation of Helicobacter pylori (contacting caffeine) to administer the inhibited pharmaceutical composition, which includes a compound as claimed in the scope of the patent application or a pharmaceutically acceptable compound 19. Salts.-Individuals who need to block sodium channels to give the blocked pharmaceutical composition, ## ^ ^ ^ ^, including a compound 20. Or the pharmaceutically acceptable salts of the compound. Species, and individuals who want to block sodium channels to give the blocked pharmaceutical composition, its &amp; b ^ ^ ^, including a patent application scope The compound of item 10 or one of the compounds is a pharmaceutically acceptable salt. 427 1236477 6. The scope of the application for a patent is changed, and the body is 22: =, the compound is-pharmaceutically acceptable. "Salt:, 1. = 1 To alleviate neuropathic pain: = academic composition 'which includes-a species such as the scope of application for patents i. 23-, a species of Yangbei compound-pharmaceutically acceptable salts. (, Used as-local anesthetic Pharmaceutical composition and includes one: 一 物 _ 一- 24 · -A pharmaceutical composition for use as a local anesthetic, which includes a compound such as the scope of application for patent No. 10 or a pharmaceutically acceptable salt of the compound. 25 · -A kind of a drug in need of treatment The etiology involves the individual with pathological factors, diseases or clinical conditions of glutamate release, which is used for administering the medicine to the therapeutic composition, which includes a compound such as the item of the scope of patent application or one of the compounds. Acceptable salts. 26 · —A pharmaceutical composition for the treatment of any individual who needs to treat any pathological, disease or clinical condition that involves the release of glutamate, which is Including a compound as claimed in item 10 of the patent application or a pharmaceutically acceptable salt of the compound. 27. A pharmaceutical composition as item 25 in the patent application, wherein the pathology, disease or clinical condition is selected From the following groups: psychiatric diseases, hormonal symptoms, brain damage caused by metabolism, sulfite oxidase deficiency, hepatic encephalopathy related to liver failure, vomiting, spasms, Epilepsy, patented tinnitus, pain, and drug abuse and withdrawal. The pharmaceutical composition of patented item 26, wherein the pathology, disease or clinical condition is selected from the group consisting of: psychiatric disease, hormonal disease Symptoms, metabolism-induced brain damage, inadequate sulfite oxidase, hepatic encephalopathy associated with liver failure, vomiting, convulsions, epilepsy, tinnitus, pain, and drug abuse and withdrawal. 29 · -species-requires treatment Any one of the individuals involved in the pathology of neuronal damage to administer the pharmaceutical composition for the treatment includes a compound such as the first item of the patent application scope or a pharmaceutically acceptable salt of the compound. 30.-A pharmaceutical composition for administering to a subject in need of treating any pathology involving neuronal damage, which comprises a compound as claimed in item 10 of the patent application or a pharmaceutically acceptable compound Salt. 3 1 · The pharmaceutical composition according to item 29 of the application, wherein the pathology is selected from the group consisting of: · Alzheimer's disease, Huntington's disease or Parkinson's disease, virus (including HIV) -induced neurodegeneration, amyotrophic lateral sclerosis (ALS), nuclear paralysis (supra-nuclear palsy), inferior oligopontine cerebellar atrophy (〇pCA), and environmental and exogenous neurotoxins The role. 32. The pharmaceutical composition of claim 30 in the scope of patent application, wherein the pathology is selected from the group consisting of: Alzheimer's disease, Huntington's disease or Parkin's disease, virus (including HI V) -induced neurodegeneration, amyotrophic spinal lateral sclerosis (ALS), paralysis of the nucleus, mandibular corpus callosum bridge 1236477 Six patent application scope magnetic], cerebral atrophy (OPCA) 'and ring sound 彳 L ^ J Yi Xiong and the role of exogenous neurotoxins. 33. 34. A pharmaceutical composition for the treatment of an arrhythmia to be administered to an individual 'includes a compound such as the item i in the scope of the patent application to form a pharmaceutically acceptable salt of the compound. A single individual to administer the treatment to a non-pharmaceutical composition requiring arrhythmia, which includes a compound such as straight hair ^ m &gt; Yong T ° month patent scope of the 10th compound or one of the compounds pharmaceutically Acceptable salts. 35. A pharmaceutical composition for administration of epilepsy to an individual in need of treatment, which comprises a compound such as the one in the scope of the patent application, or a pharmaceutically acceptable salt thereof. 36.-A pharmaceutical composition for treating epilepsy in an individual who needs to treat the epilepsy, which includes a compound such as the scope of patent application No. 10: a pharmaceutically acceptable salt of the compound.
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